1,2,4-Amino-triazine derivatives as pyruvate dehydrogenase kinase inhibitors: Synthesis and pharmacological evaluation

: Among the different hallmarks of cancer, deregulation of cellular metabolism turned out to be an essential mechanism in promoting cancer resistance and progression. The pyruvate dehydrogenase kinases (PDKs) are well known as key regulators in cells metabolic process and their activity was found to be overexpressed in different metabolic alerted types of cancer, including the high aggressive pancreatic ductal adenocarcinoma (PDAC). To date few PDK inhibitors have been reported, and the different molecules developed are characterized by structural chemical diversity. In an attempt to find novel classes of potential PDK inhibitors, the molecular hybridization approach, which combine two or m…

Interleukin 3- receptor targeted exosomes inhibit in vitro and in vivo chronic myelogenous Leukemia cell growth

Despite Imatinib (IM), a selective inhibitor of Bcr-Abl, having led to improved prognosis in Chronic Myeloid Leukemia (CML) patients, acquired resistance and long-term adverse effects is still being encountered. There is, therefore, urgent need to develop alternative strategies to overcome drug resistance. According to the molecules expressed on their surface, exosomes can target specific cells. Exosomes can also be loaded with a variety of molecules, thereby acting as a vehicle for the delivery of therapeutic agents. In this study, we engineered HEK293T cells to express the exosomal protein Lamp2b, fused to a fragment of Interleukin 3 (IL3). The IL3 receptor (IL3-R) is overexpressed in CML…

Studi di Modellistica Molecolare e Sintesi di Sistemi Indolotriazolopirimidinici

Nortopsentin heteroanalogues: syntheses and antitumor activity

A multivariate analysis on HIV-1 protease inhibitors and resistance induced by mutation

Molecular modelling studies on new series of DNA-interactive annelated pyrrolo-pyrimidines

Pirrolo[3,4-h]chinolinoni: Potenziali Agenti Fotochemioterapici

AMINO-HETEROCYCLES AS SYNTHONS FOR THE SYNTHESIS OF POTENTIAL ANTICANCER AGENTS

Thiazole Analogues of the Marine Alkaloid Nortopsentin as Inhibitors of Bacterial Biofilm Formation

Anti-virulence strategy is currently considered a promising approach to overcome the global threat of the antibiotic resistance. Among different bacterial virulence factors, the biofilm formation is recognized as one of the most relevant. Considering the high and growing percentage of multi-drug resistant infections that are biofilm-mediated, new therapeutic agents capable of counteracting the formation of biofilms are urgently required. In this scenario, a new series of 18 thiazole derivatives was efficiently synthesized and evaluated for its ability to inhibit biofilm formation against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 25923 and S. aureus ATCC 6538 a…

PYRROLO-FUSED HETROCYCLES WITH PHOTOCHEMOTHERAPEUTIC ACTIVITY

Synthesis of the New Ring System 2-Oxo-[1,4]oxazino[3,2-e]indole, Heteroanalogue of Angelicin

A convenient synthesis of the 2-oxo-[1,4]oxazino[3,2-e]indole ring system, an heteroanalogue of Angelicin, is reported. Our synthetic approach consisted of the annelation of the oxazine ring on the indole moiety using 4-amino-5-hydroxy indoles as building blocks. The antiproliferative activity of the new compounds either in the dark or under UVA irradiation was investigated.

An overview on the recent developments of 1,2,4-triazine derivatives as anticancer compounds

The synthesis, the antitumor activity, the SAR and, whenever described, the possible mode of action of 1,2,4-triazine derivatives, their N-oxides, N,. N'-dioxides as well as the benzo- and hetero-fused systems are reported. Herein are treated derivatives disclosed to literature from the beginning of this century up to 2016. Among the three possible triazine isomers, 1,2,4-triazines are the most studied ones and many derivatives having remarkable antitumor activity have been reported in the literature and also patented reaching advanced phases of clinical trials.

Pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrimidine and pyrrolo[3,4-d] [1,2,3]triazolo[1,5-a]pyrimidine. New tricyclic ring systems of biological interest

Derivatives of the new ring system pyrrolo[3,4-e][1,2,3] triazolo[1,5-a]pyrimidine 6 were prepared in high yields in one step by reaction of 3-azidopyrrole 3 and substituted acetonitriles. Compound 6b rearranged, upon heating in dimethyl sulfoxide in the presence of water, to pyrrolo[3,4-d][1,2,3]triazolo-[1,5-a]pyrimidine 7.

THIOPYRANO[2,3-E]INDOL-2-ONES: ANGELICIN HETEROANALOGUES WITH POTENT PHOTOANTIPROLIFERATIVE ACTIVITY

A new class of compounds, the thiopyrano[2,3-e]indol-2-ones, bioisosters of the angular furocoumarin angelicin, was synthesized with the aim of obtaining new photochemotherapeutic agents. In particular 7,8-dimethyl-thiopyranoindolone 6c s showed a remarkable phototoxicity and a great dose UVA dependence reaching IC(50) values at submicromolar level. This latter photoinduced a massive apoptosis and a remarkable photodamage to lipids and proteins. Although it did not intercalate DNA, it was able to cause photooxidation of DNA bases.

Synthesis of isoindolo[1,4]benzoxazinone and isoindolo[1,5]benzoxazepine: two new ring systems of pharmaceutical interest

Abstract Two new ring systems, isoindolo[1,4]benzoxazinone and isoindolo[1,5]benzoxazepine, were conveniently synthesized through cyclization of suitably substituted isoindole derivatives. Some of the new compounds exhibited antiproliferative activity against a wide range of human tumor cell lines with GI 50 mean values at low micromolar level (3.72–5.13 μM).

“QSPR, Sintesi ed Attività Biologica di Nuovi Derivati del Sistema Tetraciclico Indolo[3,2-e][1,2,3]triazolo[1,5-a]pirimidinico.”

INDOLO[2,3-B]PYRROLYZIN-8(1H)ONE: A NEW RING SYSTEM WITH POTENTIAL ANTIMITOTIC ACTIVITY

Docking of Indolo- and Pyrrolo-pyrimidines to DNA New DNA-interactive Polycycles from 2-Amino-indoles/pyrroles and BMMA

1,3,5-Triazines: A promising scaffold for anticancer drugs development

This review covering literature reports from the beginning of this century to 2016 describes the synthetic pathways, the antitumor activity, the structure-activity relationship and, whenever reported, the possible mechanism of action of 1,3,5-triazine derivatives as well as of their hetero-fused compounds. Many 1,3,5-triazine derivatives, both uncondensed and hetero-fused, have shown remarkable antitumor activities and some of them reached clinical development.

MADoSPRO: a new approach to molecular modelling studies on a series of DNA minor groove binders

The aim of this work was devoted to develop a method to predict Delta G values for a series of minor groove binders. Starting from a matrix of docking dataset for 10 minor groove binders (known and not) to 20 DNA fragments, with various sequences, it was possible to analyze the interaction modes and to calculate the Delta G value for new derivatives through MADoSPRO procedure. The method allowed, through the QSPR analysis, to characterize the type of interactions in such complexes, that was demonstrated to be related to quantum chemical and electrostatic descriptors, in agreement with the information available in literature on the structural requirements of specific minor groove ligands. Mo…

Eight-membered Rings with Two Heteroatoms 1,2. In Comprehensive Heterocyclic Chemistry III, AR Katritzky, CA Ramsden, EFV Scriven and RJK Taylor, Eds.; Elsevier: Oxford

This chapter deals with heterocine rings with two heteroatoms in a 1,2-relationship, namely 1,2-diazocine, 2H-1,2-oxazocine, 2H-1,2-thiazocine, 1,2-dioxocin, 1,2-oxathiocin, and 1,2-dithiocin. This chapter covers the literature from 1996 to 2006 and also reports those articles published in 1995 which were not reported in CHEC-II(1996). In this edition, in addition to the uncondensed derivatives, eight-membered 1,2-heterocycles fused to five-, six-, and seven-membered carbocycles or heterocycles are covered, although in one case a four-membered fused cycle was occasionally reported. Bridged heterocines, which actually constitute the majority of the compounds reported, are covered as well. Th…

Nucleophilic substitutions in the isoindole series as a valuable tool to synthesize derivatives with antitumor activity

Abstract A novel synthetic approach to the synthesis of 3-substituted isoindoles through nucleophilic substitution of 3-halo derivatives by charged carbon, and neutral nitrogen, oxygen, and sulfur nucleophiles, assisted by a 1-acyl group, is reported. Aryl-thio-isoindoles, obtained through a direct nucleophilic substitution with sulfur nucleophiles, showed cytotoxic activity, with GI50 values from micromolar to sub-micromolar concentrations, against the total number of cell lines investigated.

CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

Summary Limited therapeutic options are available for advanced colorectal cancer (CRC). Herein, we report that exposure to a neo-synthetic bis(indolyl)thiazole alkaloid analog, nortopsentin 234 (NORA234), leads to an initial reduction of proliferative and clonogenic potential of CRC sphere cells (CR-CSphCs), followed by an adaptive response selecting the CR-CSphC-resistant compartment. Cells spared by the treatment with NORA234 express high levels of CD44v6, associated with a constitutive activation of Wnt pathway. In CR-CSphC-based organoids, NORA234 causes a genotoxic stress paralleled by G2-M cell cycle arrest and activation of CHK1, driving the DNA damage repair of CR-CSphCs, regardless…

4,5,6,9-TETRAHYDROPYRROLO[2',3'-3,4]CYCLOEPTA[1,2-d]ISOSSAZOLE, PROCESS FOR THEIR PRODUCTION AND THEIR USES AS ANTITUMOR AGENTS

The present invention concerns the synthesis of compounds bearing the PYRROLO[2',3'-3,4]CYCLOEPTA[1,2-d]ISOSSAZOLE structure, and their use for the treatment of pathologies having hyperproliferative features included those having neoplastic nature.

NUOVI DERIVATI PIRROLO[2,3-B]PIRIDINICI SOSTITUITI, PROCEDIMENTO PER LA LORO PREPARAZIONE E LORO IMPIEGO TERAPEUTICO.

2-Triazenoazaindoles: Α novel class of triazenes inducing transcriptional down-regulation of EGFR and HER-2 in human pancreatic cancer cells

Pancreatic cancer is a complex malignancy arising from the accumulation of genetic and epigenetic defects in the affected cells. Standard chemotherapy for patients with advanced disease shows only modest effects and is associated with considerable toxicity. Overexpression or aberrant activation of members of the epidermal growth factor receptor tyrosine kinase family, which includes EGFR and HER-2, occurs frequently and is associated with multiple drug resistance and decreased patient survival. In this study, we have investigated the therapeutic potential of AS104, a novel compound of the triazene class, with potential inhibitory effects on EGFR. We found that treatment of cells with AS104 …

Photochemotherapeutic haterocyclic agents having antiproliferative and antineoplastic activity

Pyrazolo[3,4-h]quinolin-2-ones with photobiological properties

Aza-isoindolo and isoindolo-azaquinoxaline derivatives with antiproliferative activity

Abstract Three new ring systems, pyrido[2′,3′:3,4]pyrrolo[1,2- a ]quinoxalines, pyrido[3′,2′:3,4]pyrrolo[1,2- a ]quinoxalines and pyrido[2′,3′:5,6]pyrazino[2,1- a ]isoindoles, were synthesized through an aza-substitution on the already active isoindolo-quinoxaline system and in particular in the position 7 or 4 of the isoindole moiety and in position 5 of the quinoxaline portion. All new compounds were screened by the National Cancer Institute (Bethesda, MD) against a panel of 60 human tumor cell lines. Biological results of the most active derivatives, with pGI 50 values between 7.09 and 7.27, confirmed the importance of the presence of methoxy substituents for biological activity. The ant…

Synthesis and Antiproliferative Activity of 2,5-bis(3′-Indolyl)pyrroles, Analogues of the Marine Alkaloid Nortopsentin

2,5-bis(3′-Indolyl)pyrroles, analogues of the marine alkaloid nortopsentin, were conveniently prepared through a three step procedure in good overall yields. Derivatives 1a and 1b exhibited concentration-dependent antitumor activity towards a panel of 42 human tumor cell lines with mean IC50 values of 1.54 μM and 0.67 μM, respectively. Investigating human tumor xenografts in an ex-vivo clonogenic assay revealed selective antitumor activity, whereas sensitive tumor models were scattered among various tumor histotypes.

Synthesis and antitumor activities of 1,2,3-triazines and their benzo- and heterofused derivatives

1,2,3-Triazines are a class of biologically active compounds that exhibit a broad spectrum of activities, including antibacterial, antifungal, antiviral, antiproliferative, analgesic and anti-inflammatory properties. This review, which covers the literature from the end of last century to 2016, treats, through a comprehensive, systematic approach, the 1,2,3-triazine and related benzo- and hetero-fused derivatives possessing antitumor activity. Their efficacy, combined with a simple synthesis confers to these molecules a great potential as scaffold for the development of antitumor compounds.

7-Azaindole-fused heterocycles with antitumor activity

Synthesis of the new ring system 6,8-dihydro-5H-pyrrolo[3,4-h]quinazoline

Abstract A convenient synthesis of the pyrrolo[3,4- h ]quinazoline ring system is reported. Our synthetic approach consisted of the annelation of a pyrimidine ring to an isoindole moiety using tetrahydroisoindole-4-ones as building blocks. The antiproliferative activity of the new compounds was investigated and one of them showed antitumor activity against all the 59 tested cell lines at micromolar concentrations (1.46–18.4 μM).

Five-Membered Heterocyclic Rings and Their Fused Derivatives

Polycondensed nitrogen heterocycles. Part24. Pyrrolo[3,4-c]isoquinolinone by thermal rearrangement of a pyrrolylbenzotriazinone

Rearrangement under acidic conditions of the pyrrolylbenzotriazinone 7 afforded the pyrrolylbenzamides 10 and 11. By thermal rearrangement instead, the first fully aromatic derivative of the pyrrolo[3,4-c]isoquinoline ring system 9 was obtained.

[1,2]oxazole[5,4-e]isoindoles as promising drugs for anticancer chemotherapy

‘Interrupted’ diazotization of 3-aminoindoles and 3-aminopyrroles

Abstract ‘Interrupted’ diazotization of 3-aminoindoles and 3-aminopyrroles, achieved by quenching with cold water immediately after the addition of nitrite, led, in good yields, to stable compounds whose structures were identified to be the diazonium species with nitrate as the counter ion, which show no saline character.

Preclinical Activity of New [1,2]Oxazolo[5,4-e]isoindole Derivatives in Diffuse Malignant Peritoneal Mesothelioma

A series of 22 derivatives of the [1,2]oxazolo[5,4-e]isoindole system were synthesized through an efficient and versatile procedure that involves the annelation of the [1,2]oxazole moiety to the isoindole ring, producing derivatives with a wide substitution pattern. The structure-activity relationship indicates that the N-4-methoxybenzyl group appears crucial for potent activity. In addition, the presence of a 6-phenyl moiety is important and the best activity is reached with a 3,4,5-trimethoxy substituent. The most active compound, bearing both the structural features, was able to inhibit tumor cell proliferation at nanomolar concentrations when tested against the full NCI human tumor cell…

Synthesis and Antitumor Properties of 2,5-Bis(3'-indolyl) thiophenes: Analogues of Marine Alkaloid Nortopsentin

A series of 11 bis-indolylthiophenes of formula I were obtained by cyclization of bis-indole 1,4-diketones using Lawesson''s reagent. Derivs. I (R = OMe, R1 = SO2Ph), I (R = OMe, R1 = Me), I (R = Cl, R1 = Me), and I (R = OMe, R1 = H) were selected to be evaluated in the full panel of about 60 human tumor cell lines derived from nine human cancer cell types and showed antiproliferative activity generally in the micromolar range. The most sensitive cell lines were: CCRF-CEM, MOLT-4, HL60 (TB), and RPMI-8226 of the leukemia subpanel, HT29 and HCC-2998 cell lines of the colon sub-panel, NCI-H522 of the non-small cell lung cancer sub-panel, LOX IMVI of the melanoma sub-panel, and UO-31 of the re…

SYNTHESIS OF 3,5-BIS(3'-INDOLYL)ISOXAZOLES, ANALOGUES OF MARINE ALKALOID NORTOPSENTIN

Synthesis and antiproliferative activity of the ring system [1,2]oxazolo[4,5-g]indole.

Brand new ring: A series of 27 derivatives of the new ring system [1,2]oxazolo[4,5-g]indole were conveniently prepared and tested at the NCI for antiproliferative studies. Several of them showed good inhibitory activity toward all tested cell lines, reaching GI50 values generally at the micromolar and sub-micromolar levels and in some cases at nanomolar concentrations. The mean GI50 values, calculated on the full panel, were in the range 0.25-7.08 μM.

PYRROLO[3,4-H]QUINOLIN-2-ONES AS NEW POTENTIAL PHOTOCHEMOTERAPEUTIC DRUGS

Synthesis and photocytotoxic activity of [1,2,3]triazolo[4,5-h][1,6]naphthyridines and [1,3]oxazolo[5,4-h][1,6]naphthyridines

Abstract [1,2,3]Triazolo[4,5-h][1,6]naphthyridines and [1,3]oxazolo[5,4-h][1,6]naphthyridines were synthesized with the aim to investigate their photocytotoxic activity. Upon irradiation, oxazolo-naphtapyridines induced light-dependent cell death at nanomolar/low micromolar concentrations (EC50 0.01–6.59 μM). The most photocytotoxic derivative showed very high selectivity and photocytotoxicity indexes (SI = 72–86, PTI>5000), along with a triplet excited state with exceptionally long lifetime (18.0 μs) and high molar absorptivity (29781 ± 180 M−1cm−1 at λmax 315 nm). The light-induced production of ROS promptly induced an unquenchable apoptotic process selectively in tumor cells, with mitoch…

Pyrazolo[3,4-h]quinolines promising photosensitizing agents in the treatment of cancer.

A new series of pyrazolo[3,4-h]quinolines, heteroanalogues of angelicin was conveniently prepared with a broad substitution pattern. A large number of derivatives was obtained and the cellular photocytotoxicity was evaluated in vitro against 5 different human tumor cell lines with GI50 values reaching the nanomolar level (14.52e0.04 mM). Selected compounds were able to photoinduce a massive cell death with the involvement of mitochondria. Their photodamage cellular targets were proteins and lipids and they did not cause any kind of DNA photodamage. This latter event is of considerable importance in the modulation of long term side effects, generally associated with the use of classical furo…

Docking of indolo- and pyrrolo-pyrimidines to DNA. New DNA-interactive polycycles from amino-indoles/pyrroles and BMMA

New indolo- and pyrrolo-pyrimidines of type 1-4 were studied for their ability to form stable complexes with DNA fragments. The calculated free energies of binding were found in the range -8.39 ÷ -16.72 Kcal/mol. The docking studies revealed a common binding mode with the chromophore intercalated between GC base pairs whereas the side chain lies along the minor groove.

Polycondensed nitrogen heterocycles. XXII. A new synthesis of 5,6-dihydro-7H-pyrazolo[1,5-d][1,4]benzodiazepin-6-ones

A new synthesis of 2-methyl-9-R'-10-R-5,6-dihydro-7H-pyrazolo[1,5-d][1,4]benzodiazepin-6-ones (4a-c) is deserved. Reaction of ethyl hydrazinoacetate hydrochloride with 1,3-diketones 1a-c gave both 3-methyl-5-(4R'-5-R-2-nitrophenyl)pyrazol-1-yl-acetate acids (2a-c) and the corresponding ethyl esters 3a-c. Reduction with the appropiate reducing agent of compounds 2a-c and 3a-c directly gave the title compounds. Compound 4a showed insecticidal properties against the house fly.

ChemInform Abstract: Polycondensed Nitrogen Heterocycles. Part 25. Aminopyrrolo(1,2-f) phenanthridines by Decomposition of 2-(3-Azidophenyl)-1-arylpyrroles.

Acid catalyzed decomposition of the azido derivatives 4a-c gave rise to amino-hydroxy-phenylpyrroles of type 7 and 8 upon hydrolysis of the intermediate aryl nitrenium ions, together with the hydrogen abstraction compounds of type 3. The aminopyrrolo[1,2-f]phenanthridines 10, 11, and 12 were obtained by treatment with TFMSA of the azide 4d in which the ring being attacked was made more nucleophilic by the introduction of the methoxy group.

Synthesis and antiproliferative activity of thiazolyl-bis-pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, nortopsentin analogues.

Two new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and indole units were both substituted by 7-azaindole moieties or one indole unit was replaced by a 6-azaindole portion, were efficiently synthesized. Compounds belonging to both series inhibited the growth of HCT-116 colorectal cancer cells at low micromolar concentrations, whereas they did not affect the viability of normal-like intestinal cells. A compound of the former series induced apoptosis, evident as externalization of plasma membrane phosphatidylserine (PS), and changes of mitochondrial trans-membrane potential, while blocking the cell cycle in G2/M phase. In contr…

Synthesis and Antitumor Activity of New Thiazole Nortopsentin Analogs

New thiazole nortopsentin analogs in which one of the two indole units was replaced by a naphthyl and/or 7-azaindolyl portion, were conveniently synthesized. Among these, three derivatives showed good antiproliferative activity, in particular against MCF7 cell line, with GI50 values in the micromolar range. Their cytotoxic effect on MCF7 cells was further investigated in order to elucidate their mode of action. Results showed that the three compounds act as pro-apoptotic agents inducing a clear shift of viable cells towards early apoptosis, while not exerting necrotic effects. They also caused cell cycle perturbation with significant decrease in the percentage of cells in the G0/G1 and S ph…

Annelated pyrrolo-pyrimidines from amino-cyanopyrroles and BMMAs as leads for new DNA-interactive ring systems.

The efficient one-pot synthesis of several new tricyclic systems of type 1 and 2, obtained from the reaction of substituted 2-amino-3-cyanopyrroles and 3-amino-4-cyanopyrroles with BMMAs, is reported. The duration and yields of the reaction strongly depend on the reactivity of the starting pyrrole and on the size of the ring to be formed. Mechanist features of the reaction were investigated and proposed by studying also the reactivity of a 3-aminopyrrole-2,4-dicyano substituted. The method reported represents the first example of the use of BMMA reagents in combination with pyrrole derivatives and allows an easy and versatile entry to a large number of hitherto unknown pyrrolo-pyrimidines f…

3-(6-Phenylimidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1H-Indole Derivatives as New Anticancer Agents in the Treatment of Pancreatic Ductal Adenocarcinoma

A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC50) ranging from 5.11 to 10.8 &micro

ChemInform Abstract: Polycondensed Nitrogen Heterocycles. Part 24. Pyrrolo(3,4-c) isoquinolinone by Thermal Rearrangement of a Pyrrolylbenzotriazinone.

Rearrangement under acidic conditions of the pyrrolylbenzotriazinone 7 afforded the pyrrolylbenzamides 10 and 11. By thermal rearrangement instead, the first fully aromatic derivative of the pyrrolo[3,4-c]isoquinoline ring system 9 was obtained.

Biological Evaluation of the Antiproliferative and Anti-migratory Activity of a Series of 3-(6-Phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1H-indole Derivatives against Pancreatic Cancer Cells*

Heterocyclic rings are recognized as key components of many natural, semi-synthetic and synthetic molecules with a broad spectrum of biological activities. Among these molecules, the indole and imidazo[2,1-b][1,3,4]thiadiazole systems have recently been described as useful scaffolds for the design of anticancer agents. Herein the antitumor activity of a series of 3-(6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1H-indoles, designed as hybrid structures, was assessed. Seven out of 10 compounds (1a-g) were submitted to National Cancer Institute (NCI). Remarkably, compound 1g showed antiproliferative activity against the full panel of sixty human cancer lines, with half-maximal inhibitory conc…

Nanostructured Lipid Carriers-Containing Anticancer Compounds: Preparation, Characterization, and Cytotoxicity Studies

This article describes the development of nanostructured lipid carriers (NLC) as colloidal carriers for two antitumor compounds that possess a remarkable antineoplastic activity. But their limited stability and low solubility in water could give a very low parenteral bioavailability. Results revealed an enhancement of the cytotoxicity effect of drug-loaded NLC on human prostate cancer (PC-3) and human hepatocellular carcinoma (HuH-6, HuH-7) cell lines with respect to that of both free drugs. Results of characterization studies strongly support the potential application of these drugs-loaded NLC as prolonged delivery systems for lipophilic drugs by several administration routes, in particula…

Pyrrolo[2,3-h]quinolinones: synthesis and photochemotherapic activity.

A series of derivatives of the new ring system pyrrolo[2,3-h]quinoline-2-one was synthesized and evaluated as photoreagents toward cultured human tumor cells. Remarkable phototoxycity resulted for some derivatives, especially those bearing the phenyl group at the 7-position.

Quality characteristic and in vitro digestibility study of barley flour enriched ditalini pasta

Synthesis of the new oligopeptide pyrrole derivative isonetropsin and its one pyrrole unit analogue

We have designed and synthesized isonetropsin and its one pyrrole unit analogue in which the amine and carbonyl groups have been switched in positions 2 and 4, respectively instead of 4 and 2 positions of the natural antibiotic netropsin.

Eight-membered heterocycles with two heteroatoms in a 1,2-relationship of interest in medicinal chemistry

Abstract This chapter treats 1,2-diheterocines, eight membered heterocyclic systems with two heteroatoms, N, O and S, in an 1,2 relationship, exhibiting biological properties and exhaustively covers the literature from 2007 to the end of November 2019. In this period of time 1,2-diazocine, 1,2-oxazocine, 1,2-dioxocin and 1,5-dithiocin ring systems had derivatives exhibiting pharmacological activities. No articles on biological properties have been reported for 1,2-thiazocines and 1,2-oxathiocins. Besides uncondensed derivatives, 1,2-diheterocines fused with five-, six-, and seven-membered carbocycles or heterocycles have been reviewed, as well as bridged 1,2-diheterocines.

3-CHLOROETHYL-PYRROLO[2,1-D][1,2,3,5]TETRAZINES: SYNTHESIS AND ANTITUMOR ACTIVITY

Eight-membered heterocycles with two heteroatoms in a 1,5-relationship of interest in medicinal chemistry

Abstract This review deals with 1,5-diheterocines that exhibited biological properties and covers comprehensively the literature from 2007 to the end of February 2019. Among the six possible heterocyclic systems belonging to the eight-membered rings with two heteroatoms, N, O, and S, five had derivatives showing pharmacological activities: 1,5-diazocines, 1,5-oxazocines, 1,5-thiazocines, 1,5-dioxocins, and 1,5-dithiocins. Instead, literature reported no articles dealing with 1,5-oxathiocins of interest in medicinal chemistry. In addition to uncondensed derivatives, 1,5-diheterocines fused to five- and six-membered carbocycles or heterocycles are covered. Bridged 1,5-diheterocines are covere…

In vitro digestion of beta glucan enriched pasta: polysaccharide molecular characterization and antioxidant activity of bioaccessible fraction.

BIOSYNTHESIS OF HEROCYCLES. FROM ISOLATION TO GENE CLUSTER

This book describes biosynthetic methods to synthesize heterocyclic compounds, offering a guide for the development of new drugs based on natural products. The authors explain the role of natural products in chemistry and their formation along with important analytical methods and techniques for working with heterocycles. • Covers methods and techniques: isotopic labelling, enzymes and mutants, and pathway identification • Provides a thorough resource of information specifically on heterocyclic natural products and their practical biosynthetic relevance • Explains the role of natural products in chemistry and their formation • Discusses gene cluster identification and the use of biogenetic …

SISTEMI PIRROLICI AD ATTIVITA' FOTOCHEMIOTERAPICA

Novel 1H‑Pyrrolo[2,3‑b]pyridine Derivative Nortopsentin Analogues: Synthesis and Antitumor Activity in Peritoneal Mesothelioma Experimental Models

In this study, we describe the synthesis of new nortopsentin analogues, 1H-pyrrolo[2,3-b]pyridine derivatives and their biological effects in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rare and rapidly fatal disease, poorly responsive to conventional therapies. The three most active compounds, 1f (3-[2-(5-fluoro-1-methyl-1H-indol-3- yl)-1,3-thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine), 3f (3-[2-(1H-indol-3-yl)-1,3- thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b]pyridine), and 1l (3-[2-(5-fluoro-1- methyl-1H-indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b] pyridine), which were shown to act as cyclin-dependent kinase 1 inhibitors, consistently reduced DMPM cell p…

Synthesis, antitumor activity and CDK1 inhibiton of new thiazole nortopsentin analogues

A new series of thiazole nortopsentin analogues was conveniently synthesized with fair overall yields. The antiproliferative activity of the new derivatives was tested against different human tumor cell lines of the NCI full panel. Four of them showed good antitumor activity with GI(50) values from micro to nanomolar level. The mechanism of the antiproliferative effect of these derivatives, was pro-apoptotic, being associated with externalization of plasma membrane phosphatidylserine and DNA fragmentation. The most active and selective of the new thiazoles confined viable cells in G2/M phase and markedly inhibited in vitro CDK1 activity. (C) 2017 Elsevier Masson SAS.

SINTESI ED ATTIVITÀ ANTITUMORALE DI ANALOGHI PENTATOMICI DELLA NORTOPSENTINA

Pyrrolo[2,1-d][1,2,3,5]tetrazine-4(3H)-ones with Potent Antitumor Activity

ChemInform Abstract: Polycondensed Nitrogen Heterocycles. Part 23. Pyrrolo(3,2-c)cinnolines by a Japp-Klingemann-Type Reaction.

Pyrrolo[3,2-c]cinnoline derivatives were obtained by an unusual Japp-Klingemann reaction involving an intramolecular azadehalogenation on the pyrrole nucleus. Such an azadehalogenation represents the first example of Japp-Klingemann reaction in which the extrusion of positive chlorine ion is verified.

3-Diazopyrroles—IV. Structure determination using 13C NMR spectroscopy

Abstract On the basis of the 13 C NMR chemical shifts, it is proposed that, although b is the major canonical structure, structure c , in which a negative charge resides at C-3, provides an important contribution to the resonance stabilization of the 3-diazopyrroles, 1–4 .

Pyrrolo[2,1-d][1,2,3,5]tetrazine-4(3H)-ones, a new class of azolotetrazines with potent antitumor activity.

Pyrrolo[2,1-d][1,2,3,5]tetrazinones 10a-o, compounds that hold the deaza skeleton of the antitumor drug temozolomide, were prepared by reaction of 2-diazopyrroles 9 and isocyanates. Such a synthetic route represents, among those leading to azolotetrazinones reported so far, the only possible one since attempts to cyclize to the title ring system 2-amino-1-carbamoylpyrroles 11 or the mono substituted 2-triazenopyrrole 12 failed. Compounds 10 were screened at the National Cancer Institute (NCI) for their activity against a panel of about 60 human tumor cell lines. Most of them possess remarkable antineoplastic activity having GI(50) values in the low micromolar or sub-micromolar range and rea…

Polycondensed nitrogen heterocycles. Part21. Complete13C NMR assignment of annelated phenanthridines

Two-dimensional nmr techniques were used for the complete assignment of 13C nmr spectra of pyrrolo-[1,2-f]-, pyrazolo[1,5-f]-, and 1,2,4-triazolo[1,5-f]phenanthridines.

PYRAZOLO[3,4-h]QUINOLIN-2-ONES WITH POTENTIAL ANTITUMOR ACTIVITY

SYNTHESIS OF 3,5-BIS(3'-INDOLYL)PYRAZOLES, ANALOGUES OF NORTOPSENTIN

An efficient synthesis of pyrrolo[3',2':4,5]thiopyrano[3,2-b]pyridin-2-one: a new ring system of pharmaceutical interest

Abstract A series of pyrrolo[3′,2′:4,5]thiopyrano[3,2- b ]pyridin-2-ones 4 was prepared in good yields by reacting enaminoketones with cyanomethylene active compounds such as phenylsulfonylacetonitrile, benzoylacetonitrile, and malononitrile. Derivatives of the title ring system were tested by the National Cancer Institute of Bethesda against a panel of about 60 human tumor cell lines, and one of them showed inhibitory activity against all cancer cell lines reaching on 48% of them GI 50 values at submicromolar level and on the majority of the remaining ones in the low micromolar concentration.

PYRROLO[3',2':4,5]THIOPYRANO[3,2-b]PYRIDIN-2-ONES WITH POTENTIAL ANTITUMOR ACTIVITY

Pyrido[4′,3′:4,5]pyrrolo[2,1-d][1,2,3,5]tetrazines, a new class of Temozolomide heteroanalogues

A series of derivatives of new ring system pyrido[4’,3’:4,5]pyrrolo[2,1-d] [1,2,3,5]tetrazine was obtained from moderate to excellent yields by reaction of 2-diazo-3-ethoxycarbonyl-pyrrolo[2,3- c]pyridine with alkyl- or aryl-isocyanates in dichlorometane at room temperature or at 50 °C under microwave irradiation.

Isoindolo[1,2-a]quinoxaline derivatives with potent antitumor activity.

SYNTHESIS OF NEW OLIGOPEPTIDE PYRROLE DERIVATIVES

SYNTHESIS AND PHOTOCHEMIOTHERAPEUTIC ACTIVITY OF THIOPYRANO[2,3-E]INDOL-2-ONES

A series of derivatives of the new ring system thiopyrano[2,3-e]indol-2-one was prepared with the aim of obtaining new photochemotherapeutic drugs. Biological screenings were performed on this new class of photoactivable drugs and a strong antiproliferative effect was observed upon irradiation with UVA light. The compound bearing a methyl substituent at the pyrrole nitrogen resulted as the most interesting showing IC50 in the nanomolar range.

Eight-membered Rings with Two Heteroatoms 1,5

The chapter of the third edition of Comprehensive Heterocyclic Chemistry (CHEC III) 12.24 titled ‘Eight-membered Rings with two Heteroatoms 1,5’ deals with diheterocines rings with two heteroatoms in a 1,5 relationship, namely 1,5-diazocine, 1,5-oxazocine, 1,5-thiazocine, 1,5-dioxocin, 1,5-oxathiocin, and 1,5-dithiocin. This chapter covers the literature from 1996 to 2006 and also reports those articles published in 1995 which were not reported in CHEC-II(1996). In this edition, in addition to the uncondensed derivatives, eight-membered 1,5-heterocycles fused to five-, six-, and seven-membered carbocycles or heterocycles are covered. Bridged diheterocines, which actually constitute the majo…

A synthetic approach to new polycyclic ring system of biological interest through domino reaction: indolo[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine

Abstract The title indolo-triazolo-pyrimidines were obtained from 3-azidoindoles and can be used as models for the design of DNA-interactive compounds. Hetero-domino reaction of azidoindoles/pyrroles and acetonitriles constitutes the synthetic entry to annelated 1,2,3-triazolo[1,5- a ]pyrimidines.

PYRROLO[3,2-H]QUINAZOLINE AS PHOTOCHEMOTHERAPEUTIC AGENTS

3-[2-(1H-Indol-3-yl)-1,3-thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridine: a new series of kinase inhibitors

New syntheses of condensed heterocycles from isoxazole derivatives. V. Pyrrolo[3,4-b]pyridin-4-ones

Hydrogenolysis with Raney-Nickel or iron powder in acetic acid of 2,5-diphenyl-4-nitro-3-(3,5-R,R-4-isoxazolyl)pyrrolyl ketones, prepared by the Grignard reaction of 2,5-diphenylpyrrole and 3,5-R,R-4-isoxazolecarboxilic acid chlorides followed by nitration, afforded directly the desired 6H-pyrrolo[3,4-b ]pyridin-4-ones.

Polycondensed nitrogen heterocycles. Part13. Pyrrolo[3,2-b]indole by intramolecular nucleophilic substitution reaction in the pyrrole series

An intramolecular nucleophilic substitution in the pyrrole series has been generalized. The behaviour of nitro, chlorine, bromine and iodine as leaving groups towards the nucleophilic amino group was observed. An acid catalyzed mechanism has been proposed.

Isoindolo[2,1-c]benzo[1,2,4]triazines: a new ring system with antiproliferative activity.

Abstract A series of isoindolo-benzo-triazines of type 4 was obtained by diazotization of 2-(2-aminoaryl)-1-cyanoisoindoles 3a – j . All the synthesized derivatives were screened by the National Cancer Institute (NCI, Bethesda, USA), for in vitro antitumor activity against a 3-human cancer cell line panel consisting of MCF7 (breast), NCI-H460 (lung), and SF-268 (CNS). Derivatives 4a , f , i , j were selected to be evaluated in the full panel of about 50 human tumor cell lines derived from nine human cancer cell types and showed antiproliferative activity generally in the micromolar range. The most sensitive cell lines were: MOLT-4 and SR of the leukemia subpanel, A549/ATCC and EKVX of the n…

Synthesis and antitumor activity of new 7-azaindole derivative nortopsentin analogues

ChemInform Abstract: Polycondensed Nitrogen Heterocycles. Part 22. Pyrrolo(3,4-d)-1,2,3-triazines: A New Ring System as Potential Antineoplastic Agent.

Diazotization of the 3-aminopyrrole-4-carboxamides 6a,b under different conditions directly led to the new ring system pyrrolo[3,4-d]-1,2,3-triazine in excellent yields through an intramolecular coupling reaction. In all the cases it was impossible to isolate the intermediate 3-diazopyrroles.

Eight-membered Rings with Two Heteroatoms 1,2

This chapter deals with heterocine rings with two heteroatoms in a 1,2-relationship, namely 1,2-diazocine, 2H-1,2-oxazocine, 2H-1,2-thiazocine, 1,2-dioxocin, 1,2-oxathiocin, and 1,2-dithiocin. This chapter covers the literature from 1996 to 2006 and also reports those articles published in 1995 which were not reported in CHEC-II(1996). In this edition, in addition to the uncondensed derivatives, eight-membered 1,2-heterocycles fused to five-, six-, and seven-membered carbocycles or heterocycles are covered, although in one case a four-membered fused cycle was occasionally reported. Bridged heterocines, which actually constitute the majority of the compounds reported, are covered as well. Th…

Pyrrolo[2,3-h]quinolinones: A new ring system with potent photoantiproliferative activity

A new class of compounds, the pyrrolo[2,3-h]quinolin-2-ones, nitrogen isosters of the angular furocoumarin Angelicin, was synthesized with the aim of obtaining new photochemotherapeutic agents with increased antiproliferative activity and lower undesired toxic effects than the lead compound. Two synthetic pathways were approached to allow the isolation both of the dihydroderivatives 10-17 and of the aromatic ring system 23. Compounds 10-17 showed a remarkable phototoxicity and a great UVA dose dependence reaching IC(50) values at submicromolar level. Intracellular localization of these compounds has been evaluated by means of fluorescence microscopy using tetramethylrhodamine methyl ester a…

Synthesis of [1,2]oxazolo[5,4-e]indazoles as antitumour agents

Abstract A series of 40 derivatives of the [1,2]oxazolo[5,4-e]indazoles ring system have been prepared with good yields using a versatile and convenient route. Annelation of the [1,2]oxazole ring on the indazole-4-one system was achieved by reaction of the corresponding enaminoketones with hydroxylamine hydrochloride. Derivatives of the title ring system were tested by the National Cancer Institute of Bethesda and one of them (13t) showed growth-inhibitor activity against all the 54 human tumour cell lines generally at low micromolar concentrations.

New Topsentin analogs as inhibitors of biofilm formation

SYNTHESIS OF 2,5-BIS(3'-INDOLYL)-FURANS, ANALOGUES OF NORTOPSENTIN

New 1,2,4-oxadiazole nortopsentin derivatives with cytotoxic activity

New analogs of nortopsentin, a natural 2,4-bis(3&prime

Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms

There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the deriv…

PYRROLO[3,4-G]INDAZOLE A NEW RING SYSTEM WITH POTENTIAL ANTITUMOR ACTIVITY

Sintesi di Oligopeptidi Pirrolici Isomeri della Distamicina e della Netropsina

Techniques for Biosynthesis

AZAINDOLO-FUSED HETEROCYCLES: SYNTHESIS AND ANTITUMOR ACTIVITY

DERIVATI ISOINDOLO-CHINOSSALINICI AD ATTIVITA' ANTITUMORALE, PROCEDIMENTO PER LA LORO PRODUZIONE E LORO USO

Studi di Docking su Isomeri della Distamicina e della Netropsina

Isoxazolo[5,4-e]isoindole a new ring system with potent antitumor activity

Seven-, Eight-Membered and Larger Heterocyclic Rings and Their Fused Derivatives

Sintesi chimica di nuovi agenti fotochemioterapici eterociclici, con attività antiproliferativa compresa quella di natura neoplastica

La presente invenzione riguarda la sintesi di nuovi analoghi dell’angelicina, pirrolo[3,2-h]chinolinoni, per la cura di patologie a carattere iperproliferativo comprese quelle di natura neoplastica. La cura si basa sull’azione combinata dei pirrolo[3,2-h]chinolinoni e luce UV-A attraverso una nuova tipologia di fotochemioterapia. Questi nuovi derivati hanno dimostrato interessante fototossicità in vitro nei confronti di cellule tumorali umane ma senza indurre un fotodanno al DNA, il quale rappresenta la principale causa degli effetti collaterali della terapia PUVA.

Pyrano[2,3-e]isoindol-2-ones, new angelicin heteroanalogues

A convenient synthesis of the pyrano[2,3-e]isoindol-2-one ring system, an heteroanalogue of angelicin, is reported. Our synthetic approach consists of the annelation of the pyran ring on the isoindole moiety using 5-dialkylamino- or 5-hydroxymethylene intermediates as building blocks. The photoantiproliferative activity of the new derivatives was studied. Some of them bearing the benzyl group at the 8 position were active with IC(50) in the micromolar range. Cell cytotoxicity involves apoptosis, alteration of cell cycle profile and membrane photodamage.

Derivati di chinossalina, metodi per la loro produzione e loro uso come agenti antitumorali

Sintesi ed Attivita’ Fotobiologica di Tiopirano[2,3-c]indol-2-oni

2,5-BIS(3'-INDOLYL)THIOPHENES, ANALOGUES OF MARINE ALKALOID NORTOPSENTIN

Pyrimido[5,4-c]pyrrolo[2,1-a]isoquinoline: a new potential DNA-interactive ring system

The acid catalyzed decomposition of the azide 9 failed to give the title compounds, which were however obtained by a Pschorr-type cyclization on reactive 1-(6-aminopyrimidin-5-yl)-pyrroles of type 13. Derivatives of type 14 and 15 were fully characterized by NMR data. Theoretical calculations demonstrated that the new compounds possess properties suitable for DNA- intercalation.

Synthesis of substituted isoindolo[2,1-a]quinoxalin-6-yl–amino and 6-imino-5-yl thiourea derivatives

A series of substituted 1-(5-bromopyridin-2-yl)-3-[2-(isoindolo[2,1-a]quinoxalin-6- ylamino)ethyl]thiourea and 1-(5-bromopyridin-2-yl)-3-[2-(6-iminoisoindolo[2,1-a]quinoxalin- 5(6H)-yl)ethyl]thiourea derivatives were prepared in good yields (63-85%) by reaction between the corresponding amino compounds with 5-bromo-2-isothiocyanatopyridine. All thiourea derivatives, tested for inhibition of HIV-1 RT, showed no significant antiviral activity.

Study on the mechanism of action of antitumor photochemotherapic agents by means of docking and QSPR analysis

1,2,4-Oxadiazole topsentin analogs as staphylococcal biofilm inhibitors targeting the bacterial transpeptidase sortase A

The inhibition or prevention of biofilm formation represents an emerging strategy in the war against antibiotic resistance, interfering with key players in bacterial virulence. This approach includes the inhibition of the catalytic activity of transpeptidase sortase A (Srt A), a membrane enzyme responsible for covalently attaching a wide variety of adhesive matrix molecules to the peptidoglycan cell wall in Gram-positive strains. A new series of seventeen 1,2,4-oxadiazole derivatives was efficiently synthesized and screened as potential new anti-virulence agents. The ability of inhibiting biofilm formation was evaluated against both Gram-positive and Gram-negative pathogens. Remarkably, all…

Synthesis of 3-triazenopyrroles

Abstract The 3-triazenopyrroles, a new class of pyrrole derivatives, were synthesized in quantitative yield by coupling 3-diazopyrroles with secondary amines.

BIS-INDOLYL-5-MEMBER HETEROCYCLES ANALOGUES OF MARINE ALKALOID NORTOPSENTIN: SYNTHESES AND ANTINEOPLASTIC ACTIVITY

Inhibitors of antibiotic resistance mechanisms: clinical applications and future perspectives

Bacterial strains responsible for antibiotic resistant infections are increasing in an alarming way and the evolution of resistance mechanisms seems to be unstoppable. In the past decade, many efforts have been made in order to counteract this phenomenon but very few compounds have reached clinical trials. The development of new classes of antibiotics able to overcome the main bacterial drug resistance mechanisms is urgently required to counter the imminent danger of a postantibiotic era.

4-AZAINDOLE[2,1-D][1,3,5]TETRAZINE-4(3H)-ONES, A NEW CLASS OF AZOLOTETRAZINES AS POTENTIAL ANTITUMOR AGENTS

Pyrrolo[2,1-d][1,2,3,5]tetrazinones deaza analogues of temozolomide with potent antitumor activity

The title compounds, that hold the deaza skeleton of temozolomide, exhibited potent in vitro antiproliferative activity. An evaluation of such a biological activity indicates that the mode of action of these compounds differs from that of temozolomide and is also mechanistically unrelated to that of any known antitumor drug.

A Multivariate Analysis of HIV-1 Protease Inhibitors and Resistance Induced by Mutation

This paper describes the use of the multivariate statistical procedure principal component analysis as a tool to explore the inhibitory activity of classes of protease inhibitors (PIs) against HIV-1 viruses (wild type and more-frequent single mutants, V82A, V82F, and I84V) and against protease enzymes. The analysis of correlations between biological activity and molecular descriptors or similarity indexes allowed a reliable classification of the 51 derivatives considered in this study. The best results were obtained in the case of the I84V mutant for which a high number of predictions was achieved. On this basis, this statistical approach is proposed as a reliable method for the prediction …

New Tricyclic System of Biological Interest Thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine Trough Domino Reactions of 2-Azidothiophene.

7-AZAINDOLO[1,2-c][1,2,3]BENZOTRIAZINA UN NUOVO SISTEMA ETEROCICLICO A POTENZIALE ATTIVITA’ ANTITUMORALE

Tricyclic heterocycles with antiproliferative activity

Composti a struttura ossazolica, procedimenti per la loro produzione e loro impiego per la cura di patologie a carattere iperproliferativo

La presente invenzione riguarda composti che presentano nella loro struttura il sistema eterociclico [1,2]Ossazolo[5,4-e]isoindolo, un procedimento per la oro produzione e il loro impiego per la cura di patologie a carattere iperproliferativo comprese quelle di natura neoplastica. I nuovi derivati saggiati al National Cancer Institute di Bethesda su un 60 linee cellulari umane divise in 9 sottopannelli (mammella, ovaie, polmone, colon, SNC, melanoma, leucemia, rene, prostata), hanno mostrato attività antiproliferativa da micro a nanomolare, rivelando alcuni derivati particolarmente promettenti.

2-substituted-[1,3]thiazolo[4,5-e]isoindoles as kinases inhibiting compounds

Synthesis of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one

Derivatives of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one were prepared in four steps starting from substituted benzonitriles bearing a functionalized amino group in the adjacent position. The unsubstituted- and the dimethoxy-pyrrolizinoindolones 5a and 5b exhibited modest activity against the HL-60(TB) human leukemia cell line, whereas the N-methylated dimethoxy-pyrrolizinoindolone 6b showed to be selective against MOLT-4 leukemia, A549/ATCC, HOP-92, and NCI-H460 non-small cell lung cancer, and CAKI-1 renal cancer cell lines.

SYNTHESIS OF 2,5-BIS(3'-INDOLYL)-PYRROLES, DEAZA-ANALOGUES OF NORTOPSENTIN

Quality characteristics and in vitro digestibility study of barley flour enriched ditalini pasta

A ditalini pasta with a mixture of durum wheat and beta-glucan enriched barley flour (BF) (60/40%, w/w) was found to have a final content of 5% beta-glucan (BF-ditalini). Main quality parameters of BF-ditalini, water uptake and starch-protein texture, were comparable with those of 100% durum wheat ditalini (control). After in vitro simulated intestinal digestion, the content of beta-glucan in the post intestinal (PI) supernatant of BF-ditalini processed with its cooking water (soup) was six fold higher than that of pasta asciutta. BF-ditalini soup, but not pasta asciutta, strongly delayed the hydrolysis of the starch, without difference of viscosity between PI supernatant and control. PI su…

Isoindolo[2,1-c]benzo[1,2,4]triazine: a New Ring System with Potential Antitumor Activity

11H‑Pyrido[3′,2′:4,5]pyrrolo[3,2‑c]cinnoline and Pyrido[3′,2′:4,5]pyrrolo[1,2‑c][1,2,3]benzotriazine: Two New Ring Systems with Antitumor Activity

Derivatives of new ring systems 11H-pyrido[3',2':4,5]pyrrolo[3,2-c]cinnoline and pyrido[3',2':4,5]pyrrolo[1,2-c][1,2,3]benzotriazine have been prepared from the key intermediates 2-(1H-pyrrolo[2,3-b]pyridin-2-yl)anilines in excellent yields (94-99%) and screened by the National Cancer Institute (Bethesda, MD) on about 60 human tumor cell lines derived from nine cancer cell types. The tested compounds exhibited antiproliferative activity against all the human cell lines, showing comparable MG_MID (mean graph midpoint) values in the range of 0.74-1.15 μM. A particular efficacy was observed against the leukemia subpanel (GI50 = 0.73-0.0090 μM). Flow cytometric analysis of the cell cycle demons…

SYNTHESIS AND ANTITUMOR ACTIVITY OF 2,5-BIS(3'-INDOLYL)-FURANS AND 3,5-BIS(3'-INDOLIY)-ISOXAZOLES, NORTOPSENTIN ANALOGUES

Abstract A series of novel 2,5-bis(3′-indolyl)furans and 3,5-bis(3′-indolyl)isoxazoles were synthesized as antitumor agents. The antiproliferative activity was evaluated in vitro toward diverse human tumor cell lines. Initially 5 isoxazoles and 3 furan derivatives were tested against a panel of 10 human tumor cell lines and the most active derivatives 3c and 4a were selected to be evaluated in an extended panel of 29 cell lines. By exhibiting mean IC50 values of 17.4 μg/mL (3a) and 20.5 μg/mL (4c), in particular 4c showed a high level of tumor selectivity toward the 29 cell lines.

Novel 1H-pyrrolo[2,3-b]pyridine derivative nortopsentin analogues: synthesis and antitumor activity in peritoneal mesothelioma experimental models.

In this study, we describe the synthesis of new nortopsentin analogues, 1H-pyrrolo[2,3-b]pyridine derivatives and their biological effects in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rare and rapidly fatal disease, poorly responsive to conventional therapies. The three most active compounds, 1f (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3-thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine), 3f (3-[2-(1H-indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b]pyridine), and 1l (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b] pyridine), which were shown to act as cyclin-dependent kinase 1 inhibitors, consistently reduced DMPM cell prol…

SYNTHESIS AND PHOTOBIOLOGICAL ACTIVITY OF PYRROLO-FUSED HETEROCYCLES

Therapeutic Strategies To Counteract Antibiotic Resistance in MRSA Biofilm‐Associated Infections

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as one of the leading causes of persistent human infections. This pathogen is widespread and is able to colonize asymptomatically about a third of the population, causing moderate to severe infections. It is currently considered the most common cause of nosocomial infections and one of the main causes of death in hospitalized patients. Due to its high morbidity and mortality rate and its ability to resist most antibiotics on the market, it has been termed a “superbug”. Its ability to form biofilms on biotic and abiotic surfaces seems to be the primarily means of MRSA antibiotic resistance and pervasiveness. Importantly, more tha…

ChemInform Abstract: Synthesis of the New Ring System Pyrrolizino[2,3-b]indol-4(5H)-one.

A variety of pyrrolizinoindolones (VIII) is synthesized as demonstrated for derivative (VIIIa).

Synthesis of the New Ring System Bispyrido[4',3':4,5]pyrrolo [1,2-a:1',2'-d]pyrazine and Its Deaza Analogue

Derivatives of the new ring systems bispyrido[4',3':4,5]pyrrolo[1,2-a:1',2'-d] pyrazine-6,13-dione and its deaza analogue pyrido[4'',3'':4',5']pyrrolo-[1',2':4,5]pyrazino [1,2-a]indole-6,13-dione were conveniently synthesized through a four-step sequence. Symmetrical derivatives of the former ring system were obtained through self condensation. On the other hand, condensation of 6-azaindole carboxylic acid with indole 2-carboxylic acid afforded the deaza analogue ring system. Derivatives of the title ring system were tested by the National Cancer Institute (Bethesda, MD, USA) and four of them exhibited modest activity against MCF7 (a breast cancer cell line) and/or UO-31 (a renal cancer cel…

Thiazoles, Their Benzofused Systems, and Thiazolidinone Derivatives: Versatile and Promising Tools to Combat Antibiotic Resistance.

Thiazoles, their benzofused systems, and thiazolidinone derivatives are widely recognized as nuclei of great value for obtaining molecules with various biological activities, including analgesic, anti-inflammatory, anti-HIV, antidiabetic, antitumor, and antimicrobial. In particular, in the past decade, many compounds bearing these heterocycles have been studied for their promising antibacterial properties due to their action on different microbial targets. Here we assess the recent development of this class of compounds to address mechanisms underlying antibiotic resistance at both bacterial-cell and community levels (biofilms). We also explore the SAR and the prospective clinical applicati…

ChemInform Abstract: 3-Diazopyrroles: Key Intermediates in the Synthesis of Antineoplastic Agents

SYNTHESIS OF TETRACYCLIC SYSTEMS WITH POTENT ANTITUMOR ACTIVITY

Synthesis of Triazenoazaindoles: a New Class of Triazenes with Antitumor Activity

Despite improvements in the treatment and prevention of cancer, the number of new diagnoses continues to rise; this has fuelled substantial interest in the development of new and effective chemotherapeutic agents. Compounds of the triazene class, such as dacarbazine, have been used in the clinical management of many cancer types including brain, leukemia, and melanoma. A new compound class bearing a triazenoazaindole scaffold was synthesized with the aim of identifying new antiproliferative agents. Compounds 5 a-g and 6 a-c were screened against a panel of human tumor cell lines, and two of them, 5 e and 5 f, showed cytotoxicity (GI(50) range: 2.2-8.2 μM) in all cell lines. These two compou…

4,5,6,9-tetraidropirrolo[2',3':3,4] cicloepta[1,2-d] isossazoli, procedimento per la loro produzione e loro uso come antitumorali

La presente invenzione riguarda derivati a struttura 4,5,6,9- tetraidropirrolo[2',3':3,4]cicloepta[1,2-d]isossazolica, procedimenti per la loro produzione e il loro uso per la cura di patologie a carattere iperproliferativo comprese quelle di natura neoplastica. I nuovi derivati saggiati al National Cancer Institute di Bethesda su un pannello di circa 60 linee cellulari umane divise in 9 sottopannelli (mammella, ovaie, polmone, colon, SNC, melanoma, leucemia, rene, prostata), hanno mostrato attività antiproliferativa da micro a nanomolare, rivelando alcuni derivati particolarmente promettenti

New Tetracyclic Ring System of Biological Interest Indolo[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine through domino reactions of 2-azidoindole

Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells

A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 μM, and 0.29–12.2 μM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized (SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), elici…

Eight-Membered Rings With Two Heteroatoms 1,3

Eight-membered rings with two heteroatoms in a 1,3-relationship, namely 1,3-diazocine, 2H-1,3-oxazocine, 2H-1,3-thiazocine, 4H-1,3-dioxocin, 4H-1,3-oxathiocin, and 4H-1,3-dithiocin, are discussed in this chapter, that covers the literature from 2007 to October 2020 (SciFindern search) and reports the chemistry of uncondensed derivatives, heterocines fused to carbocycles and heterocycles, as well as bridged heterocines. Among eight-membered 1,3-diheterocines, 1,3-diazocines and 1,3-oxazocines are the two largest classes, based on the number of publications, mostly due to the studies of the synthesis of these cyclic systems, their pharmacological properties and/or their important industrial a…

Studi di Molecular Modelling su Derivati del Nuovo Sistema Eterociclico DNA-interattivo Isoindolo[2,1-c]benzo[1,2,4]triazina

ChemInform Abstract: Pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrimidine and Pyrrolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine. New Tricyclic Ring Systems of Biological Interest.

Derivatives of the new ring system pyrrolo[3,4-e][1,2,3] triazolo[1,5-a]pyrimidine 6 were prepared in high yields in one step by reaction of 3-azidopyrrole 3 and substituted acetonitriles. Compound 6b rearranged, upon heating in dimethyl sulfoxide in the presence of water, to pyrrolo[3,4-d][1,2,3]triazolo-[1,5-a]pyrimidine 7.

2-OXO-[1,4]OXAZINO[3,2-E]INDOLE: A NEW RING SYSTEM WITH POTENTIAL PHOTOBIOLOGICAL PROPERTIES

Synthesis of novel 1,2,4-oxadiazole topsentin analogs with antitumor activity

Synthesis of novel 1,2,4-oxadiazole topsentin analogs with antitumor activity

PYRANO[2,3-E]ISOINDOL-2-ONE: A NEW RING SYSTEM WITH POTENTIAL PHOTOBIOLOGICAL PROPERTIES

Pyrrolotetrazinones deazaanalogues of temozolomide induce apoptosis in Jurkat cell line: involvement of tubulin polymerization inhibition.

Pyrrolotetrazinones are a new class of azolotetrazinones endowed with a high, remarkable antiproliferative activity in human tumor cultured cells. They hold the deaza skeleton of the antitumor drug temozolomide, although preliminary investigations indicated a different mechanism of action. To understand their mechanism(s) of action along with their target at molecular level, four derivatives were selected on the basis of their activity on a panel of human tumor cell lines and they were investigated in depth in a T leukemia cell line (Jurkat). Flow cytometric analysis of cell cycle after treatment with pyrrolotetrazinones has demonstrated that they were able to induce an arrest of the cell c…

Apoptosis induction in HL-60 leukemia cells by photoexcited tiopyrano[2,3]indol-2-ones

PHOTOCHEMOTHERAPEUTIC AGENTS: DESIGN, SYNTHESIS AND ANTITUMOR ACTIVITY

Isoindolo[2,1-a]quinoxaline derivatives, novel potent antitumor agents with dual inhibition of tubulin polymerization and topoisomerase I.

Isoindoloquinoxalines 4 and 5 were obtained by refluxing 2-(2'-aminoaryl)-1-cyanoisoindoles 3a- e in acetic or formic acid. All derivatives were screened by the National Cancer Institute (Bethesda, MD) for the in vitro one dose primary anticancer assay against a 3-cell line panel. Compounds 4a- e, screened against a panel of about 60 human tumor cell lines, showed remarkable antineoplastic activity; they had GI 50 values in the low micromolar or submicromolar range and reached, in the case of 4c, nanomolar concentrations on 88% of the 59 tested cell lines. Flow cytometric analysis of cell cycle after treatment with 4c demonstrated an arrest of the cell cycle in G2/M phase. This effect was a…

Polycondensed nitrogen heterocycles. Part25. Aminopyrrolo[1,2-f]-phenanthridines by decomposition of 2-(3-azidophenyl)-1-arylpyrroles

Acid catalyzed decomposition of the azido derivatives 4a-c gave rise to amino-hydroxy-phenylpyrroles of type 7 and 8 upon hydrolysis of the intermediate aryl nitrenium ions, together with the hydrogen abstraction compounds of type 3. The aminopyrrolo[1,2-f]phenanthridines 10, 11, and 12 were obtained by treatment with TFMSA of the azide 4d in which the ring being attacked was made more nucleophilic by the introduction of the methoxy group.

Quality, functional and sensory evaluation of pasta fortified with extracts from Opuntia ficus-indica cladodes

Background The stems of Opuntia ficus-indica, known as cladodes, are a rich source of soluble fibers, which makes them an important candidate for the production of functional foods. Tagliatelle of durum wheat fortified with Opuntia cladode extract (OCE) at different levels of addition (10-30%, v/w) was prepared on a laboratory scale and quality characteristics and sensory acceptability were assessed. Results The main quality parameters (optimal cooking time, swelling index, cooking loss, dry matter) and sensory analysis on a nine-point hedonic scale were comparable with those of the control pasta sample (no added OCE) when durum wheat was supplemented with OCE at up to 20% (v/w). An in vitr…

Synthesis and antiproliferative activity of substituted 3[2-(1H-indol-3-yl)-1,3-thiazol-4-yl]-1H-pyrrolo[3,2-b]pyridines, marine alkaloid nortopsentin analogues

A large number of indolyl-4-azaindolyl thiazoles, nortopsentin analogues, were conveniently synthesized. The antiproliferative activity of the new derivatives was examined against four human tumor cell lines with different histologic origin. Seven derivatives consistently reduced the growth of the experimental models independently of TP53 gene status and exhibited the highest activity against the malignant peritoneal mesothelioma (STO) cell line. The most active compound of this series acts as a CDK1 inhibitor, and was found to cause cell cycle arrest at G 2 /M phase, to induce apoptosis by preventing the phosphorylation of survivin in Thr 34 and to increase the cytotoxic activity of paclit…

ChemInform Abstract: Polycondensed Nitrogen Heterocycles. Part 17. Isoxazolo(4,3-d)pyrazolo-(3,4-f)(1,2,3)triazepine. A New Ring System.

The title compounds were prepared by nitration of compounds 2, reduction of the dinitro derivatives 4 and diazotization of the diamino derivatives 6 followed by an intramolecular coupling reaction. Compound 4a showed good activity against Salmonella cholerasuis and Clostridium perfringens bacteria.

Synthetic small molecules as anti-biofilm agents in the struggle against antibiotic resistance

Abstract Biofilm formation significantly contributes to microbial survival in hostile environments and it is currently considered a key virulence factor for pathogens responsible for serious chronic infections. In the last decade many efforts have been made to identify new agents able to modulate bacterial biofilm life cycle, and many compounds have shown interesting activities in inhibiting biofilm formation or in dispersing pre-formed biofilms. However, only a few of these compounds were tested using in vivo models for their clinical significance. Contrary to conventional antibiotics, most of the anti-biofilm compounds act as anti-virulence agents as they do not affect bacterial growth. I…

2,6-Disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives as potent staphylococcal biofilm inhibitors.

Abstract A class of 36 new 2-(6-phenylimidazo[2,-1-b][1,3,4]thiadiazol-2-yl)-1H-indoles was efficiently synthesized and evaluated for their anti-biofilm properties against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 25923, S. aureus ATCC 6538 and Staphylococcus epidermidis ATCC 12228, and the Gram-negative strains Pseudomonas aeruginosa ATCC 15442 and Escherichia coli ATCC 25922. Many of these new compounds, were able to inhibit biofilm formation of the tested staphylococcal strains showing BIC50 lower than 10 μg/ml. In particular, derivatives 9c and 9h showed remarkable anti-biofilm activity against S. aureus ATCC 25923 with BIC50 values of 0.5 and 0.8 μg/ml, r…

3,5-bis(3'-indolyl)pyrazoles, analogues of marine alkaloid nortopsentin: synthesis and antitumor properties.

A series of 10 bis-indolylpyrazoles of type 9, 10 were obtained by cyclization of diketones 8 using hydrazine monohydrate or methylhydrazine in refluxing acetic acid/THF. Derivatives 9a,c,d were selected, by the National Cancer Institute (NCI, Bethesda, USA), to be evaluated against the full panel of about 60 human tumor cell lines derived from nine human cancer cell types and showed antiproliferative activity in the micromolar range. In particular, 9d, the most active compound was effective against all the tested cell lines with a GI(50) mean value of 3.23 microM; TGI and LC(50) values were 14.5 and 58.9 microM having positive response on 91% and 41% of the tested cell lines, respectively.

Biological evaluation of new 1,2,4-oxadiazole topsentin analogs as anticancer agents

Sintesi del Nuovo Sistema Eterociclico 7-Azaindolocinnolinico come Potenziale Agente Antineoplastico

ChemInform Abstract: An Efficient Synthesis of Pyrrolo[3′,2′:4,5]thiopyrano[3,2-b]pyridin-2-one: A New Ring System of Pharmaceutical Interest.

Derivatives of the title ring system are screened for their inhibitory activity against 60 human cancer cell lines.

Nucleophilic reactions in the indole series: displacement of bromine under phase transfer catalysis

A novel synthetic approach for the synthesis of 3-substituted indoles by nucleophilic substitution of 3-bromo derivatives under phase transfer catalysis (PTC) was reported.

HIV-1 Protease Inhibitors and Resistance Induced by Mutation. Correlation between Multivariate Analysis and Molecular Docking.

ChemInform Abstract: Synthesis of Isoindolo[1,4]benzoxazinone and Isoindolo[1,5]benzoxazepine: Two New Ring Systems of Pharmaceutical Interest.

Abstract Two new ring systems, isoindolo[1,4]benzoxazinone and isoindolo[1,5]benzoxazepine, were conveniently synthesized through cyclization of suitably substituted isoindole derivatives. Some of the new compounds exhibited antiproliferative activity against a wide range of human tumor cell lines with GI 50 mean values at low micromolar level (3.72–5.13 μM).

Polycondensed nitrogen heterocycles. Part19. Pyrrolo[1,2-f]phenanthridines by pschorr-type cyclization brought about by hypophosphorous acid

Pyrrolo[1,2-f]phenanthridines were prepared in good yields by the diazotization in acetic acid of the amines la,b and subsequent treatment with hypophosphorous acid. The necessity for hypophosphorous acid in the reaction was demonstrated.

The potential of neurotrophic tyrosine kinase (NTRK) inhibitors for treating lung cancer

Abstract: Introduction: Molecular alterations in neurotrophic tyrosine kinase (NTRK) genes have been identified in several solid tumors including lung cancer. Pre-clinical and clinical evidence suggested their potential role as oncogenic drivers and predictive biomarkers for targeted inhibition, leading to the clinical development of a new class of compounds blocking the NTRK molecular pathway, which are currently undner early clinical investigation. Area covered: This review describes the biology of the NTRK pathway and its molecular alterations in lung cancer. It focuses on the pre-clinical and clinical development of emerging NTRK inhibitors, which have shown very promising activity in e…

NUCLEOPHILIC SUBSTITUTIONS IN ISOINDOLE SERIES AS VALUABLE TOOL TO SYNTHESIZE DERIVATIVES WITH ANTITUMOR ACTIVITY

Antitumor activity of 2,5-bis-(3’-indolyl)-pyrroles, deaza-analogues of Nortopsentins

Synthesis and antiproliferative activity of [1,2,3,5]tetrazino[5,4-a]indoles, a new class of azolo-tetrazinones.

Eight derivatives of the new ring system [1,2,3,5]tetrazino[5,4-a]indole-4-one 7, were synthesised in good yields by reaction of 2-diazoindoles with alkyl or aryl isocyanates. Compounds 7 were screened at National Cancer Institute (NCI) for their activity against a panel of approximately 60 human tumour cell lines. Some of them showed antiproliferative activity having generally GI50 in the micromolar range. The most sensitive cell lines were SF-295, SNB-75 and SF-539 of the CNS cancer sub-panel, SR of the leukaemia sub-panel, UACC-62 of the melanoma sub-panel and OVCAR-4 of the ovarian cancer sub-panel. 2004 Elsevier Ltd. All rights reserved.

SYNTHESIS, REACTIVITY AND ANTINEOPLASTIC ACTIVITY OF ISOINDOLE DERIVATIVES

SYNTHESIS AND ANTITUMOR ACTIVITY OF 3-[2-PHENYL-1,3-THIAZOL-4-YL]-1H-7-AZAINDOLES

Condensed azaindole with antitumor activity

Polycondensed nitrogen heterocycles. Part 23. Pyrrolo[3,2-c]cinnolines by a japp-klingemann type reaction

Pyrrolo[3,2-c]cinnoline derivatives were obtained by an unusual Japp-Klingemann reaction involving an intramolecular azadehalogenation on the pyrrole nucleus. Such an azadehalogenation represents the first example of Japp-Klingemann reaction in which the extrusion of positive chlorine ion is verified.

In House Methodology to Assign the Mechanism of Action of New Annelated Triazolopyrimidine Derivatives with Anticancer Activity

PYRROLE SYSTEMS WITH PHOTOCHEMOTHERAPEUTIC ACTIVITY

Metabolomics-assisted discovery of a new anticancer GLS-1 inhibitor chemotype from a nortopsentin-inspired library: From phenotype screening to target identification

The enzyme glutaminase-1 (GLS-1) has shown a clear and coherent implication in the progression and exacerbation of different aggressive tumors such as glioblastoma, hepatocarcinoma, pancreas, bone, and triple-negative breast cancer. Few chemotypes are currently available as selective GLS-1 inhibitors, and still, fewer of them are at the clinical stage. In the present paper, starting from a naturally-inspired antitumor compound library, metabolomics has been used to putatively identify the molecular mechanism underlying biological activity. GLS-1 was identified as a potential target. Biochemical analysis confirmed the hypothesis leading to the identification of a new hit compound acting as a…

ISOINDOLO-FUSED HETEROCYCLES WITH ANTITUMOR ACTIVITY

Pyrrolo[3,2-h]quinazolines as Photochemotherapeutic Agents

Heteroanalogues of angelicin, pyrrolo[3,2-h]quinazolines, were synthesized with the aim of obtaining new potent photochemotherapeutic agents. Many derivatives caused a significant decrease in cell proliferation in several human tumor cell lines after irradiation with UVA light (GI(50) =15.2-0.2 μM). Their phototoxicity effected apoptosis in Jurkat cells with the involvement of mitochondria (as determined by the loss of mitochondrial membrane potential and production of reactive oxygen species) and lysosomes. The phototoxicity of these compounds could be explained by lipid peroxidation.

5H-Pirido[3’,2’:4,5]Pirrolo[3,2-c]Cinnolina un Nuovo Sistema Eterociclico a Potenziale Attività Antitumorale

PYRROLO[3,4-H]QUINAZOLINES WITH ANTITUMOR ACTIVITY

Synthesis and Antitumor Activity of 3-(2-Phenyl-1,3-thiazol-4-yl)-1H-indoles and 3-(2-Phenyl-1,3-thiazol-4-yl)-1H-7-azaindoles

Given the potent antimicrobial, antiviral, and antitumor activities of many natural products, there is an increasing interest in the synthesis of new molecules based on natural compound scaffolds. Based on a 2,4-bis(3'-indolyl)imidazole skeleton, two new series of phenylthiazolylindoles and phenylthiazolyl-7-azaindoles were obtained by Hantzsch reaction between substituted phenylthioamides and the α-bromoacetyl derivatives. Some azaindole derivatives, tested at the National Cancer Institute against a panel of ∼60 tumor cell lines derived from nine human cancer cell types, showed inhibitory effects against all cell lines investigated at micromolar to nanomolar concentrations. Two of them exh…

SINTESI DI NUOVI DERIVATI[2,3-E]ISOINDOL-2-ONI A POTENZIALE ATTIVITA' FOTOCHEMIOTERAPICA

Protonation of 3-aminopyrroles

Abstract The protonation of 3-aminopyrroles has been investigated using H and 13C n.m.r. spectroscopy. The spectral data are compatible with predominant protonation of the amino group with no evidence for protonation of the pyrrole ring.

Synthesis and antiproliferative mechanism of action of pyrrolo[3′,2′:6,7] cyclohepta[1,2-d]pyrimidin-2-amines as singlet oxygen photosensitizers

A new series of pyrrolo[3′,2′:6,7]cyclohepta[1,2-d]pyrimidin-2-amines, was conveniently prepared using a versatile and high yielding multistep sequence. A good number of derivatives was obtained and the cellular photocytotoxicity was evaluated in vitro against three different human tumor cell lines with EC50 (0.08–4.96 μM) values reaching the nanomolar level. Selected compounds were investigated by laser flash photolysis. The most photocytotoxic derivative, exhibiting a fairly long-lived triplet state (τ ∼ 7 μs) and absorbance in the UV–Vis, was tested in the photo-oxidations of 9,10-anthracenedipropionic acid (ADPA) by singlet oxygen. The photosentizing properties are responsible for the c…

New Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives Inhibit FAK Phosphorylation and Potentiate the Antiproliferative Effects of Gemcitabine Through Modulation of the Human Equilibrative Nucleoside Transporter-1 in Peritoneal Mesothelioma

Background/aim A new class of imidazo[2,1-b][1,3,4]thiadiazole compounds have recently been evaluated as inhibitors of phosphorylation of focal adhesion kinase (FAK) in pancreatic cancer. FAK is overexpressed in mesothelioma and has recently emerged as an interesting target for the treatment of this disease. Materials and methods Ten imidazo[2,1-b][1,3,4]thiadiazole compounds characterized by indole bicycle and a thiophene ring, were evaluated for their cytotoxic activity in two primary cell cultures of peritoneal mesothelioma, MesoII and STO cells. Results Compounds 1a and 1b showed promising antitumor activity with IC50 values in the range of 0.59 to 2.81 μM in both cell lines growing as …

Polycondensed nitrogen heterocycles. Part17. Isoxazolo[4,3-d]pyrazolo[3,4-f][1,2,3]triazepine. A new ring system

The title compounds were prepared by nitration of compounds 2, reduction of the dinitro derivatives 4 and diazotization of the diamino derivatives 6 followed by an intramolecular coupling reaction. Compound 4a showed good activity against Salmonella cholerasuis and Clostridium perfringens bacteria.

1,2,4-Oxadiazole Topsentin Analogs with Antiproliferative Activity against Pancreatic Cancer Cells, Targeting GSK3β Kinase.

A new series of topsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,2,4- oxadiazole moiety, was efficiently synthesized. All derivatives were pre-screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. The five most potent compounds were further investigated in various pancreatic ductal adenocarcinoma (PDAC) cell lines, including SUIT-2, Capan-1, and Panc-1 cells, eliciting EC50 values in the micromolar and sub-micromolar range, associated with significant reduction of cell migration. These remarkable results might be explained by the effects of these new topsentin analogues on epithelial-to-mesenchy…

1-methil-3H-pyrazolo[1-2-a]benzo[1-2-3-4]tetrazin-3-ones, design synthesis and biological activity of new antitumoral agents

1-Methylpyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-ones 4, synthesized in good to excellent yields, were designed as novel alkylating agents because of their peculiar chemical behavior. All derivatives showed antiproliferative activity against more than 50 types of tumor cell lines with GI50 reaching sub-micromolar values. SAR studies revealed that the presence of a chlorine atom is well-tolerated in both positions 8 and 9, whereas in the case of the methyl group, switching from the 8 to the 9 position gives rise to the most active compound of the series, 4g, either for the number of cell lines inhibited and for selectivity against leukaemia and renal cancer subpanels. COMPARE and 3D-MIND comp…

Synthesis of a new class of pyrrolo[3,4-h]quinazolines with antimitotic activity

Abstract A new series of pyrrolo[3,4- h ]quinazolines was conveniently prepared with a broad substitution pattern. A large number of derivatives was obtained and the cellular cytotoxicity was evaluated in vitro against 5 different human tumor cell lines with GI 50 values reaching the low micromolar level (1.3–19.8 μM). These compounds were able to induce cell death mainly by apoptosis through a mitochondrial dependent pathway. Selected compounds showed antimitotic activity and a reduction of tubulin polymerization in a concentration-dependent manner. Moreover, they showed anti-angiogenic properties since reduced in vitro endothelial cell migration and disrupted HUVEC capillary-like tube net…

Eight-membered heterocycles with two heteroatoms in a 1,3-relationship of interest in medicinal chemistry

This chapter deals with 1,3-diheterocines, eight-membered heterocyclic systems with two heteroatoms, N, O and S, in a 1,3 relationship, exhibiting biological properties and exhaustively covers the literature from 2007 to the end of November 2019. The biological results of 1,3-diazocines, 1,3-oxazocines, 1,3-dioxocins and 1,3-thiazocines, that are the largest class of 1,3-diheterocines, were collected together with the few results available for 1,3-oxathiocin and 1,3-dithiocin derivatives at that time.

An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge

Molecular dynamics (MD) has become increasingly popular due to the development of hardware and software solutions and the improvement in algorithms, which allowed researchers to scale up calculations in order to speed them up. MD simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile analysis over time. In recent years, the development of new tools able to deeply explore a potential energy surface (PES) has allowed researchers to focus on the dynamic nature of the binding recognition process and binding-induced protein conformational changes. Moreover, modern approaches have been demonstrated to be effective and reliable in …

ANALOGHI DELL'ALCALOIDE MARINO NORTOPSENTINA: SINTESI ED ATTIVITA' ANTITUMORALE

DIAZOPYRROLES, KEY INTERMEDIATES FOR THE SYNTHESIS OF ANTINEOPLASTIC AGENTS

Pyrrolo[2,1-d][1,2,3,5]tetrazine-4(3H)ones a new class of azolotetrazines endowed with antitumor avtivity: study of the mechanism of action

Eight-Membered Rings With Two Heteroatoms 1,5

This chapter titled “Eight-membered Rings with two Heteroatoms 1,5” deals eight-membered rings with two heteroatoms in a 1,5-relationship, namely 1,5-diazocine, 1,5-oxazocine, 1,5-thiazocine, 1,5-dioxocin, 1,5-oxathiocin, and 1,5-dithiocin and covers the literature from 2007 to October 2020 (SciFindern search) reporting the chemistry of uncondensed derivatives, diheterocines fused to carbocycles and heterocycles, as well as bridged diheterocines. Among them, the 1,5-diazocine ring system is by far the largest class, based on the number of publications which constituted the 87% of the total amount of the references reported in the range of interest of CHEC IV. Thus, 1,5-diazocines were divid…

Polycondensed nitrogen heterocycles. Part 22. Pyrrolo[3,4-d]-1,2,3-triazines: A new ring system as potential antineoplastic agent

Diazotization of the 3-aminopyrrole-4-carboxamides 6a,b under different conditions directly led to the new ring system pyrrolo[3,4-d]-1,2,3-triazine in excellent yields through an intramolecular coupling reaction. In all the cases it was impossible to isolate the intermediate 3-diazopyrroles.

Photochemotherapeutic heterocyclic agents having antiproliferative and antineoplastic activity

The present invention concerns the synthesis of new analogs of angelicins, pyrrolo[3,2-h]quinoline, for the treatment of pathologie having hyperproliferative character including those having neoplastic nature. The treatment is based on the combined action of pyrrolo[3,2-h]quinolines and UV-A light, through a clinical approach defined as PUVA (psoralen-UVA light). The most important feature of these compounds is that they exert their remarkable phototoxicity without any DNA damage, which is the main origin of the side effects of the PUVA therapy

Eight-membered Rings with Two Heteroatoms 1,3

This chapter deals with heterocine rings with two heteroatoms in a 1,3-relationship, namely 1,3-diazocine, 2H-1,3-oxazocine, 2H-1,3-thiazocine, 4H-1,3-dioxocin, and 4H-1,3-dithiocin. On the 4H-1,3-oxathiocin ring system, belonging to the diheterocine family, in the past decade, no chemistry was reported. This chapter covers the literature from 1996 to 2006 and also reports those articles published in 1995 which were not reported in CHEC-II(1996). In this edition, in addition to the uncondensed derivatives, eight-membered 1,2-heterocycles fused to five-, six-, and seven-membered carbocycles or heterocycles are covered. Bridged heterocines, which actually constitute the majority of the compou…

Pyrrolo[3,4-h]quinolinones a new class of photochemotherapeutic agents

Abstract Pyrrolo[3,4- h ]quinolin-2-ones were synthesized as nitrogen isosters of the angular furocoumarin angelicin, with the aim of obtaining new photochemotherapeutic agents with increased antiproliferative activity and lower undesired toxic effects. A versatile synthetic pathway was approached to allow the isolation of derivatives of the new ring system with a good substitution pattern on the pyrrole moiety. Photobiological screenings of the new compounds revealed a potent phototoxic effect and a great UVA dose dependence, reaching IC 50 values at submicromolar level. The induced cellular photocytotoxicity was related to apoptosis with the involvement of mitochondria and lysosomes, alte…

New topoisomerase I inhibitors with condensed-azaindole structure

Pyrrolo[3',2':6,7]cyclohepta[1,2-b]pyridines with potent photo-antiproliferative activity.

Abstract Pyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridines were synthesized as a new class of tricyclic system in which the pyridine ring is annelated to a cycloheptapyrrole scaffold, with the aim of obtaining new photosensitizing agents with improved antiproliferative activity and lower undesired toxic effects. A versatile synthetic pathway was approached, which allowed the isolation of derivatives of the title ring system with a good substitution pattern on the pyrrole moiety. Photobiological studies revealed that the majority of the new compounds showed a potent cytotoxic effect upon photoactivation with light of the proper wavelength, especially when decorated with a 2-ethoxycabonyl group an…

A Multivariate Analysis on Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors and Resistance Induced by Mutation

This paper describes the use of multivariate statistical procedure PCA as a tool to explore the inhibitory activity of classes of NNRTIs against HIV-1 viruses (wild type and more frequent mutants, Y181C, V106A, K103N, L100I) and against RT enzyme. The analysis of correlations between biological activity and molecular descriptors or similarity indexes allowed a reliable classification of the fifty five derivatives considered in this study. The best results were obtained in the case of L100I and K103N mutants for which the higher number of assignments was found when the principal components derived from the descriptors were used. On this basis this statistical approach is proposed as a reliab…

Convenient synthesis of pyrrolo[3,4-g]indazole

Abstract The synthesis of a novel class of tetrahydropyrrolo[3,4-g]indazoles is reported, by annelation of the pyrazole ring on the isoindole moiety by means of 5-hydroxymethylene tetrahydroisoindole-4-ones key intermediates, with good regioselectivity. Dihydroderivatives were also obtained by oxidation with DDQ of the corresponding tetrahydropyrrolo[3,4-g]indazoles. The growth inhibitory effect was evaluated at the National Cancer Institute of Bethesda and some derivatives showed modest activity.

Bacterial Biofilm Inhibition in the Development of Effective Anti-Virulence Strategy

There is an urgent need for new therapeutic strategies to counteract the global threat of antibiotic resistance, which has become, in recent years, one of the major public health concern. An important contribution to the microbial survival in hostile environments has been given by the capability of pathogens to form sessile communities able to adhere to biotic or abiotic surfaces, known as biofilms.

Polycondensed nitrogen heterocycles. X. 5,6,7,8-Tetrahydropyrrolo[1,2-e][1,5]benzodiazocin-7-ones. A new ring system

The synthesis of a new heterocyclic ring system is described. Condensation of 1,4-diketones 1a,b with β-alanine gave the substituted propionic acids 2a,b which upon reduction with palladium on charcoal afforded compounds 3a,b. Title compounds 4a,b were obtained by refluxing 3a,b in toluene with p-toluenesulphonic acid as catalyst.

In vitro digestion of beta glucan enriched pasta and antioxidant potential of digesta

ISOINDOLO-QUINOXALINE DERIVATIVES HAVING ANTITUMOR ACTIVITY, PROCESS FOR THEIR PRODUCTION AND THEIR USE

New isoindolo[2,1-a]quinoxaline derivatives of general formula (1 ), wherein R represents H or OH and R5 represents H or CN, have been prepared with simple procedures starting from known intermediates and resulted to posses potent in vitro antitumor activity against a panel of about 60 different human tumor cell lines belonging to several kinds of tumors, both hematological and solid. Preparations containing such derivatives as active ingredients are proposed as drugs to be employed in cancer therapy both alone and in combination with other chemotherapeutics.

SYNTHESIS OF PYRROLO[3,2-H]QUINOLINONES WITH GOOD PHOTOCHEMOTHERAPEUTIC ACTIVITY AND NO DNA DAMAGE

In the search for new photochemotherapeutic agents, a series of derivatives of the ring system pyrrolo[3,2-h]quinoline--bioisosters of the angular furocoumarin angelicin--were synthesized through a four-step synthetic approach, in reasonable overall yields. Eight of the synthesized derivatives showed a remarkable phototoxicity against a panel of four human tumor cell lines and a great dose UV-A dependence, reaching IC₅₀ values at submicromolar level. The mode of cellular death photoinduced by pyrrolo[3,2-h]quinolines was evaluated through a series of flow cytometric analysis and other tests were performed to clarify their mechanism of action.

Six-Membered Rings, and Their Fused Derivatives

ChemInform Abstract: Synthesis of the New Ring System 6,8-Dihydro-5H-pyrrolo[3,4-h]quinazoline.

Abstract A convenient synthesis of the pyrrolo[3,4- h ]quinazoline ring system is reported. Our synthetic approach consisted of the annelation of a pyrimidine ring to an isoindole moiety using tetrahydroisoindole-4-ones as building blocks. The antiproliferative activity of the new compounds was investigated and one of them showed antitumor activity against all the 59 tested cell lines at micromolar concentrations (1.46–18.4 μM).

New Tripentone Analogs with Antiproliferative Activity

Tripentones represent an interesting class of compounds due to their significant cytotoxicity against different human tumor cells in the submicro-nanomolar range. New tripentone analogs, in which a pyridine moiety replaces the thiophene ring originating the fused azaindole system endowed with anticancer activity viz 8H-thieno[2,3-b]pyrrolizinones, were efficiently synthesized in four steps with fair overall yields (34–57%). All tripentone derivatives were tested in the range of 0.1–100 μM for cytotoxicity against two human tumor cell lines, HCT-116 (human colorectal carcinoma) and MCF-7 (human breast cancer). The most active derivative, with GI50 values of 4.25 µM and 20.73 µM for HCT-116 a…

NUOVI COMPOSTI PIRAZOLO[3,4-H]CHINOLINICI, LORO PREPARAZIONE ED USO MEDICO

La presente invenzione si riferisce al campo dei composti pirazolo[3,4-h]chinolinici, loro preparazione ed uso medico, in particolare per la cura di patologie a carattere iperproliferativo comprese quelle di natura neoplastica.

ChemInform Abstract: Synthesis of 3-Triazenopyrroles.

Abstract The 3-triazenopyrroles, a new class of pyrrole derivatives, were synthesized in quantitative yield by coupling 3-diazopyrroles with secondary amines.

ISOXAZOLO[5,4-E]ISOINDOLE: A NEW RING SYSTEM WITH POTETIAL PHOTOBIOLOGICAL PROPERTIES

Water-soluble isoindolo[2,1-a]quinoxalin-6-imines: In vitro antiproliferative activity and molecular mechanism(s) of action

Abstract Water-soluble isoindoloquinoxalin (IIQ) imines and the corresponding acetates were conveniently prepared from the key intermediates 2-(2′-aminophenyl)-2H-isoindole-1-carbonitriles obtained by a Strecker reaction between substituted 1,2-dicarbaldehydes and 1,2-phenylenediamines. Both series were screened by the National Cancer Institute (Bethesda, MD) and showed potent antiproliferative activity against a panel of 60 human tumor cell lines. Several of the novel compounds showed GI50 values at a nanomolar level on the majority of the tested cell lines. Among IIQ derivatives, methoxy substituents at positions 3 and 8 or/and 9 were especially effective in impairing cell cycle progressi…

Pyrrolocycloheptaoxazole as potent antitumor agents

Itraconazole inhibits nuclear delivery of extracellular vesicle cargo by disrupting the entry of late endosomes into the nucleoplasmic reticulum

ABSTRACT Extracellular vesicles (EVs) are mediators of intercellular communication under both healthy and pathological conditions, including the induction of pro‐metastatic traits, but it is not yet known how and where functional cargoes of EVs are delivered to their targets in host cell compartments. We have described that after endocytosis, EVs reach Rab7+ late endosomes and a fraction of these enter the nucleoplasmic reticulum and transport EV biomaterials to the host cell nucleoplasm. Their entry therein and docking to outer nuclear membrane occur through a tripartite complex formed by the proteins VAP‐A, ORP3 and Rab7 (VOR complex). Here, we report that the antifungal compound itracona…

Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma

Pyruvate dehydrogenase kinases (PDKs) are serine/threonine kinases, that are directly involved in altered cancer cell metabolism, resulting in cancer aggressiveness and resistance. Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Building upon a molecular hybridization approach, a small library of 3-amino-1,2,4-triazine derivatives has been designed, synthesized, and characterized for their PDK inhibitory activity using in silico, in vitro, and in vivo assays. Biochemical screenings showed that …

Structural Manipulations of Marine Natural Products Inspire a New Library of 3-Amino-1,2,4-Triazine PDK Inhibitors Endowed with Antitumor Activity in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the main aggressive types of cancer, characterized by late prognosis and drug resistance. Among the main factors sustaining PDAC progression, the alteration of cell metabolism has emerged to have a key role in PDAC cell proliferation, invasion, and resistance to standard chemotherapeutic agents. Taking into account all these factors and the urgency in evaluating novel options to treat PDAC, in the present work we reported the synthesis of a new series of indolyl-7-azaindolyl triazine compounds inspired by marine bis-indolyl alkaloids. We first assessed the ability of the new triazine compounds to inhibit the enzymatic activity of pyruvate de…

Synthesis of 5H-pyrido[3,2-b]pyrrolizin-5-one tripentone analogs with antitumor activity

Abstract Pyrrolizinones represent an interesting class of compounds with varied degrees of structural complexity and pharmacological activity. Among these, 9H-pyrido[2,3-b]pyrrolizin-9-one, tripentone analogs, recently reported by us, showed significant antiproliferative activity against human tumor cell lines, inducing apoptosis and not affecting viability of Caco-2 differentiated in normal intestinal-like cells. Considering their interesting biological activity, their 5H-pyrido[3,2-b]pyrrolizin-5-one analogs were efficiently synthesized in good to excellent yields (61–91%). All tripentone derivatives were tested to assess their cytotoxicity against two human tumor cell lines, HCT-116 (hum…

New synthesis of condensed heterocycles from isoxazole derivatives VI. 2,5-Dimethyl-3-aeetyl-7-amino-1H-pyrrolo[3,2-b] pyridine

A new synthesis of pyrrolo[3,2-b] pyridine starting with pyrrole ring is described. The procedure allows the synthesis of 4-azaindoles bearing a sensitive group at C-7. The nitration of 4b with nitric acid and acetic anhydride at −15° gave 5. The hydrogenation of 5 led to simultaneous reduction of N-hydroxy and nitro groups and to hydrogenolysis of the isoxazole nucleus, affording an appropriate chain of atoms to building up the pyrrolo[3,2-b] pyridine ring.

3-[4-(1H-indol-3-yl)-1,3-thiazol-2-yl]-1H-pyrrolo[2,3-b]pyridines, nortopsentin Analogues with antiproliferative activity

A new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and the indole unit bound to position 2 of the thiazole ring was substituted by a 7-azaindole moiety, was efficiently synthesized. Two of the new nortopsentin analogues showed good antiproliferative effect against the totality of the NCI full panel of human tumor cell lines (~60) having GI50 values ranging from low micromolar to nanomolar level. The mechanism of the antiproliferative effect of these derivatives, investigated on human hepatoma HepG2 cells, was pro-apoptotic, being associated with externalization of plasma membrane phosphatidylserine and mitochondrial dysfunctio…

[1,2]Oxazolo[5,4-e]isoindoles as promising tubulin polymerization inhibitors

Abstract A series of [1,2]Oxazolo [5,4- e ]isoindoles has been synthesized through a versatile and high yielding sequence. All the new structures showed in the 1 HNMR spectra, the typical signal in the 8.34–8.47 ppm attributable to the H-3 of the [1,2]oxazole moiety. Among all derivatives, methoxy benzyl substituents at positions 3 and 4 or/and 5 were very effective in reducing the growth of different tumor cell lines, including diffuse malignant peritoneal mesothelioma (DMPM), an uncommon and rapidly malignancy poorly responsive to available therapeutic options. The most active compound 6j was found to impair tubulin polymerization, cause cell cycle arrest at G2/M phase and induce apoptosi…

New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation.

New thiazole nortopsentin analogues were conveniently synthesized and evaluated for their activity as inhibitors of biofilm formation of relevant Gram-positive and Gram-negative pathogens. All compounds were able to interfere with the first step of biofilm formation in a dose-dependent manner, showing a selectivity against the staphylococcal strains. The most active derivatives elicited IC50 values against Staphylococcus aureus ATCC 25923, ranging from 0.40&ndash

Pyrido[2’,3’:4,5]pyrrolo[2,1-d][1,2,3,5]tetrazine-4(3H)-ones, a new class of temozolomide heteroanalogues

Twelve derivatives of new ring system pyrido[2’,3’:4,5]pyrrolo[2,1-d][1,2,3,5]tetrazine were prepared in good yields by reaction of 2-diazo-3-ethoxycarbonyl-pyrrolo[3,2-b]pyridine with alkyl- or aryl-isocyanates. Nine derivatives, screened by the National Cancer Institute (Bethesda, MD) for the in vitro one dose primary anticancer assay against a panel of about 60 human tumor cell lines, showed no significant activity.

Preparation of monohalopyrroles

Monobromo-, monochloro- and monoiodopyrroles are obtained in excellent yields by using N-halosuccinimides in dimethylformamide as halogenating agents.

Sintesi di Nuovi Derivati 2,5-bis(3’Indolil)tiofeni, Analoghi dell’Alcaloide Marino Nortopsentina.

CCDC 1013008: Experimental Crystal Structure Determination

Related Article: Barbara Parrino, Virginia Spanò, Anna Carbone, Alessandra Montalbano, Paola Barraja, Peter Màtyus, Girolamo Cirrincione, Patrizia Diana|2014|Tetrahedron|70|7318|doi:10.1016/j.tet.2014.07.051

20 International Congresses of Heterocyclic Chemistry