New tricyclic systems as photosensitizers towards triple negative breast cancer cells.

AbstractNineteen pyrrolo[1,2-h][1,7]naphthyridinones and pyrido[2,3-c]pyrrolo[1,2-a]azepinones were synthesized as new tricyclic systems in which the pyridine ring is annelated to the 6,7-dihydroindolizin-8(5H)-one and 5,6,7,8-tetrahydro-9H-pyrrole[1,2-a]azepine-9-one moieties to obtain potential photosensitizing agents. They were tested for their photoantiproliferative activity on a triple-negative breast cancer cell line, MDA-MB-231, in the dark and under UVA light (2.0 J/cm2). We demonstrated that their toxicity, only when exposed to light, was primarily due to the generation of reactive oxygen species while their photodegradation products were not responsible for their activity. The mos…

Bioactive pyrrole-based compounds with target selectivity

The discovery of novel synthetic compounds with drug-like properties is an ongoing challenge in medicinal chemistry. Natural products have inspired the synthesis of compounds for pharmaceutical application, most of which are based on N-heterocyclic motifs. Among these, the pyrrole ring is one of the most explored heterocycles in drug discovery programs for several therapeutic areas, confirmed by the high number of pyrrole-based drugs reaching the market. In the present review, we focused on pyrrole and its hetero-fused derivatives with anticancer, antimicrobial, and antiviral activities, reported in the literature between 2015 and 2019, for which a specific target was identified, being resp…

An overview on chemical structures as ΔF508-CFTR correctors

Deletion of phenylalanine at position 508 (F508del) in the CFTR protein, is the most common mutation causing cystic fibrosis (CF). F508del causes misfolding and rapid degradation of CFTR protein a defect that can be targeted with pharmacological agents termed “correctors”. Correctors belong to various chemical classes but are generally small molecules based on nitrogen sulfur or oxygen heterocycles. The mechanism of action of correctors is generally unknown but there is experimental evidence that some of them can directly act on mutant CFTR improving folding and stability. Here we overview the characteristics of the various F508del correctors described so far to obtain indications on key ch…

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

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.

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).

Synthesis of thiazolo[5,4-b]pyridine and [1,3]thiazolo[5,4-h][1,6]naphthyridin-8-one derivatives as potential m-TOR inhibitors

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

Insight into non-nucleoside triazole-based systems as viral polymerases inhibitors

Viruses have been recognized as the etiological agents responsible for many pathological conditions ranging from asymptomatic infections to serious diseases, even leading to death. For this reason, many efforts have been made to identify selective viral targets with the aim of developing efficient therapeutic strategies, devoid of drug-resistance issues. Considering their crucial role in the viral life cycle, polymerases are very attractive targets. Among the classes of compounds explored as viral polymerases inhibitors, here we present an overview of non-nucleoside triazole-based compounds identified in the last fifteen years. Furthermore, the structure-activity relationships (SAR) of the …

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…

Current development of CFTR potentiators in the last decade

Cystic fibrosis (CF) is a genetic disorder produced by the loss of function of CFTR, a main chloride channel involved in transepithelial salt and water transport. CFTR function can be rescued by small molecules called "potentiators" which increase gating activity of CFTR on epithelial surfaces. High throughput screening (HTS) assays allowed the identification of new chemical entities endowed with potentiator properties, further improved through medicinal chemistry optimization. In this review, the most relevant classes of CFTR potentiators developed in the last decade were explored, focusing on structure-activity relationships (SAR) of the different chemical entities, as a useful tool for t…

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.

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 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.

Insight on pyrimido[5,4-g]indolizine and pyrimido[4,5-c]pyrrolo[1,2-a]azepine systems as promising photosensitizers on malignant cells

Searching for new small molecules as photosensitizing agents, we have developed a class of twenty-five pyrimido[5,4-g]indolizine and pyrimido[4,5-c]pyrrolo[1,2-a]azepines with a good substitution pattern defining a versatile synthetic pathway to approach the title ring system. All compounds were evaluated for their photocytotoxicity on a triple negative human breast cancer cell line (MDA-MB-231) in the dark and under UVA light (2.0 J/cm2). The most effective compounds exhibited a photoantiproliferative activity with IC50 values up to nanomolar ranges. Interestingly, these new developed compounds showed high selectivity towards cancerous cells with respect to non-cancerous ones. Moreover, fo…

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

Targeting multiple myeloma with natural polyphenols

Multiple myeloma (MM) is still an incurable hematologic malignancy. Although new therapeutic strategies have been developed to target different pathways in malignant cells, such as proliferation, differentiation, and apoptosis, better survival rates have also been achieved by the introduction of autologous stem cell transplantation (ASCT). Hematopoietic stem cell transplantation and novel targeted agents, such as proteasome inhibitors, monoclonal antibodies, immunomodulatory drugs, check-point inhibitors and epigenetic modulators, have significantly achieved long remission time and increased survival rates. However, most patients relapse, develop resistance, and eventually die because of re…

DNA minor groove binders: an overview on molecular modeling and QSAR approaches

Molecular recognition of DNA by small molecules and proteins is a fundamental problem in structural biology and drug design. Understanding of recognition in both sequence-selective and sequence neutral ways at the level of successful prediction of binding modes and site selectivity will be instrumental for improvements in the design and synthesis of new molecules as potent and selective gene-regulatory drugs. Minor groove is the target of a large number of non-covalent binding agents. DNA binding with specific sequences, mostly AT, takes place by means of a combination of directed hydrogen bonding to base pair edges, van der Waals interactions with the minor groove walls and generalized ele…

‘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…

Novel insights on [1,2]oxazolo[5,4‐e]isoindoles on multidrug resistant acute myeloid leukemia cell line

A series of [1,2]oxazolo[5,4‐e]isoindole derivatives was evaluated against HL‐60 cell line and its multidrug resistance (MDR) variant, HL‐60R, resistant to doxorubicin and to other P‐gp substrates by overexpressing the efflux pump. They displayed antiproliferative activities, with IC50 values ranging from 0.02 to 5.5μM. In particular, the newly synthesized compound 4k produced synergistic effects in terms of cell growth inhibition and cell death induction either in combination with a Vinca alkaloid, Vinblastine, and a Taxane, Paclitaxel in HL‐60R cells. The study of the mechanism of action indicated that all compounds showed antimitotic activity through inhibition of tubulin polymerization.…

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[1,2-f]phenanthridines and related non-rigid analogues as antiviral agents.

Abstract The pyrrolo[1,2- f ]phenanthridines 8 – 22 and the corresponding non-rigid analogues 23 – 41 were synthesised and their ability to inhibit the replication of HIV-1 was tested. Only the polycyclic derivatives 10 , 11 , and 13 showed a weak anti -HIV activity, whereas several pyrrolo-phenanthridines ( 8 , 10 , 16 – 18 ) were found to stimulate the multiplication of MT-4 cells at low concentrations. Derivative 10 demonstrated to possess the unique property of stimulating the multiplication of lymphocytes joined to HIV inhibition.

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

HSV-1 Glycoprotein D and Its Surface Receptors: Evaluation of Protein–Protein Interaction and Targeting by Triazole-Based Compounds through In Silico Approaches

Protein–protein interactions (PPI) represent attractive targets for drug design. Thus, aiming at a deeper insight into the HSV-1 envelope glycoprotein D (gD), protein–protein docking and dynamic simulations of gD-HVEM and gD-Nectin-1 complexes were performed. The most stable complexes and the pivotal key residues useful for gD to anchor human receptors were identified and used as starting points for a structure-based virtual screening on a library of both synthetic and designed 1,2,3-triazole-based compounds. Their binding properties versus gD interface with HVEM and Nectin-1 along with their structure-activity relationships (SARs) were evaluated. Four [1,2,3]triazolo[4,5-b]pyridines were i…

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.

Investigation of Isoindolo[2,1-a] quinoxaline-6-imines as Topoisomerase I Inhibitors with Molecular Modeling Methods

Background: Isoindolo[2,1-alpha] quinoxalines constitute an important class of compounds which demonstrated potent antiproliferative activity against different human tumor cell lines and topoisomerase I inhibitors. In particular, their water soluble imine or iminium salts recently synthesized showed potent growth inhibitory effect on NCI-60 tumor cell line panel and biological studies performed on the most active compounds demonstrated that they cause DNA damage via topoisomerase I poisoning. Objective: Herein, we investigate with molecular modeling methods, the common features responsible for topoisomerase I inhibition of the water-soluble isoindolo[2,1-alpha] quinoxalin-6-imines, by compa…

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…

Evaluation of [1,2]oxazolo[5,4-e]isoindoles in lymphoma cells

Anti-tubulin agents are important chemotherapeutics. Combretastatin A-4 (CA-4) emerged as lead compound for the design of new tubulin-binding agents. Its analogues 4,5-diarylisoxazoles, containing the [1,2]oxazole ring as linker of two aryl moieties, displayed higher antitubulin activity than CA-4. [1,2]oxazolo[5,4-e]isoindoles also gave excellent results reducing cell growth of NCI-60 tumor cell lines and diffuse malignant peritoneal mesothelioma (DMPM) cells. Selected derivatives showed in vivo antitumor activity at well-tolerated doses in a DMPM xenograft model. [1,2]oxazolo[5,4-e]isoindoles were screened in four lymphoma histotypes: germinal center B-cell and activated diffuse large B c…

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…

Evaluation of Fused Pyrrolothiazole Systems as Correctors of Mutant CFTR Protein.

Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named “correctors”. So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be impr…

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…

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.

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

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

Synthesis of 2H-Imidazo[2',1':2,3] [1,3]thiazolo[4,5-e]isoindol-8-yl-phenylureas with promising therapeutic features for the treatment of acute myeloid leukemia (AML) with FLT3/ITD mutations.

Despite progressive advances in understanding the molecular biology of acute myeloid leukemia (AML), the conventional therapeutic approach has not changed substantially, and the outcome for most patients is poor. Thus, continuous efforts on the discovery of new compounds with improved features are required. Following a multistep sequence, we have identified a new tetracyclic ring system with strong antiproliferative activity towards several haematological cell lines. The new compounds possess structural properties typical of inactive-state-binding kinase inhibitors and are structurally related to quizartinib which is known as type-II tyrosine kinase inhibitor. In particular, the high activi…

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

Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

AbstractThe five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp3-hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring—a phenomenon called “pseudorotation”. In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2…

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…

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.

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.

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.

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

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.

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

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

Studi di Docking su Isomeri della Distamicina e della Netropsina

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

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.

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

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 …

Exploring the anticancer activity and the mechanism of action of pyrrolomycins F obtained by microwave-assisted total synthesis

Pyrrolomycins (PMs) are a family of naturally occurring antibiotic agents, isolated from the fermentation broth of Actinosporangium and Streptomyces species. Pursuing our studies on pyrrolomycins, we performed the total synthesis of the F-series pyrrolomycins (1–4) by microwave-assisted synthesis (MAOS), thus obtaining the title compounds in excellent yields (63–69%). Considering that there is no evidence so far of the anticancer effect of this class of compounds, we investigated PMs for their antiproliferative activity against HCT116 and MCF-7 cancer cell lines. PMs showed anticancer activity at submicromolar level with a minimal effect on normal epithelial cell line (hTERT RPE-1), and the…

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

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

ChemInform Abstract: Synthesis of 5-Substituted 2,3-Dihydrobenzofurans in a One-Pot Oxidation/Cyclization Reaction.

The oxidation of N-protected p-aminophenol derivatives to quinone imides is combined with cycloaddition towards azadiene (II) in a one-pot reaction to give dihydrobenzofuran derivatives in moderate to good yields.

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…

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…

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…

Sistemi triciclici azotati ad attività fotochemioterapica

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

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

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

Pyrrolo[2',3':3,4]cyclohepta[1,2-d][1,2]oxazoles, a New Class of Antimitotic Agents Active against Multiple Malignant Cell Types

A new class of pyrrolo[2',3':3,4]cyclohepta[1,2-d][1,2]oxazoles was synthesized for the treatment of hyperproliferative pathologies, including neoplasms. The new compounds were screened in the 60 human cancer cell lines of the NCI drug screen and showed potent activity with GI50 values reaching the nanomolar level, with mean graph midpoints of 0.08-0.41 μM. All compounds were further tested on six lymphoma cell lines, and eight showed potent growth inhibitory effects with IC50 values lower than 500 nM. Mechanism of action studies showed the ability of the new [1,2]oxazoles to arrest cells in the G2/M phase in a concentration dependent manner and to induce apoptosis through the mitochondrial…

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

The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma

Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CAL…

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…

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…

Furocoumarins as multi-target agents in the treatment of cystic fibrosis.

Multi-target molecular entities, offer a path to progress both in understanding causes of disease and in defining effective small molecule treatments. Coumarin and its derivatives belong to an important group of natural compounds with diverse biological properties. They are found in vegetables and plants for which literature reports thousands of publications for the great variety of biological applications among which the photoprotective effects, thus being considered multi-targeting agents. Their furan condensed analogues constitute the family of furocoumarins, less represented in the literature, endowed with photosensitizing properties and often used for the treatment of skin diseases suc…

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

Abstract C097: Pyrrolo[2′,3′:3,4]cyclohepta[1,2-d][1,2]oxazoles: A new class of antimitotic agents

Abstract Tubulin-binding molecules constitute an important class of antineoplastic agents, with broad activity in both solid and hematologic malignancies. Oxazoles represent the core structure of many drug candidates with multiple targets, providing an attractive scaffold in medicinal chemistry. Diaryl[1,2]oxazoles have emerged as potent analogues of the antitubulin compound combretastatin A-4 (CA-4). Naphtylcombretastin and its derivatives incorporating the isoxazole moiety displayed potent cytotoxic effects and inhibition of tubulin polymerization. In particular, 5-(naphthalen-2-yl)-4-(TMP)-1,2-oxazole and 4-(naphthalen-2-yl)-5-(TMP)-1,2-oxazole showed the same inhibitory potency as napht…

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.

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).

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

GPCR Inhibition in Treating Lymphoma

G protein-coupled receptors (GPCRs) are important classes of cell surface receptors involved in multiple physiological functions. Aberrant expression, upregulation, and mutation of GPCR signaling pathways are frequent in many types of cancers, promoting hyperproliferation, angiogenesis, and metastasis. Recent studies showed that alterations of GPCRs are involved in different lymphoma types. Herein, we review the synthetic strategies to obtain GPCR inhibitors, focusing on CXCR4 inhibitors which represent most of the GPCR inhibitors available in the market or under preclinical investigations for these diseases.

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

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…

Synthesis of 5-substituted 2,3-dihydrobenzofurans in a one-pot oxidation/cyclization reaction

Variously substituted 2,3-dihydrobenzofurans have been synthesized according to a sequential one-pot oxidation/cyclization procedure between para-aminophenol derivatives and an azadiene. Variously substituted 2,3-dihydrobenzofurans have been synthesized according to a sequential one-pot oxidation/cyclization procedure between para-aminophenol derivatives and an azadiene. © 2011 Elsevier Ltd. All rights reserved.

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…

Insight on [1,3]thiazolo[4,5-e]isoindoles as tubulin polymerization inhibitors

A series of [1,3]thiazolo[4,5-e]isoindoles has been synthesized through a versatile and high yielding multistep sequence. Evaluation of the antiproliferative activity of the new compounds on the full NCI human tumor cell line panel highlighted several compounds that are able to inhibit tumor cell proliferation at micromolar-submicromolar concentrations. The most active derivative 11g was found to cause cell cycle arrest at the G2/M phase and induce apoptosis in HeLa cells, following the mitochondrial pathway, making it a lead compound for the discovery of new antimitotic drugs.

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.

Marine Anticancer Agents: An Overview with a Particular Focus on Their Chemical Classes

The marine environment is a rich source of biologically active molecules for the treatment of human diseases, especially cancer. The adaptation to unique environmental conditions led marine organisms to evolve di erent pathways than their terrestrial counterparts, thus producing unique chemicals with a broad diversity and complexity. So far, more than 36,000 compounds have been isolated from marine micro- and macro-organisms including but not limited to fungi, bacteria, microalgae, macroalgae, sponges, corals, mollusks and tunicates, with hundreds of new marine natural products (MNPs) being discovered every year.Marine-based pharmaceuticals have started to impactmodern pharmacology and diff…

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

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.

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…

NEW THERAPEUTIC AGENTS FOR THE TREATMENT OF HAEMATOLOGICAL PATHOLOGIES

Recurrence of the oxazole motif in tubulin colchicine site inhibitors with anti-tumor activity

Abstract Because of its wide spectrum of targets and biological activities, the oxazole ring is a valuable heterocyclic scaffold in the design of new therapeutic agents with anticancer, antiviral, antibacterial, anti-inflammatory, neuroprotective, antidiabetic and antidepressant properties. The presence of two heteroatoms, oxygen and nitrogen, offers possible interactions (hydrogen, hydrophobic, van der Waals or dipoles bonds) with a broad range of receptors and enzymes. Furthermore, the oxazole core conjugates low cytotoxicity with improved compound solubility and is well suited to structural modifications such as substitution with different groups and condensation to aromatic, heteroaroma…

A new Approach to Molecular Modelling Studies on a Series of DNA Minor Groove Binders

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

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…

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.

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