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

Study of Reactivity in the 1,3-Dipolar Cycloaddition Reactions Leading to New Triazolopyrrolopyrazine Ring Systems

The influence of the structural symmetry of the 2-pi double-reactive-sites component in the 1,3-dipolar cycloaddition reactions, involving nitrilimines as dipoles, was investigated. the experimental data showed that the loss of the symmetry leads to the formation of the monocycloadduct in good yields.

New imidazo[1,2-c]pyrrolo[3,2-e]pyrimidinone derivatives as potential DNA-binders

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.

The Role of 1,3-Dipolar Cycloaddition Reactions in the Design and Synthesis of Complex Heterocyclic Scaffolds with Anti-tumor/Anti-infective Activity

1,3-Dipolar cycloaddition in the synthesis of a new potential DNA-intercalating agent: indolo[3,2-e]pyrrolo[1,2-c]triazolo[1,5-a]pyrimidine

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

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…

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.

New triazolo-pyrrolopyrazine systems by 1,3-dipolar cycloaddition

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…

A convenient synthesis of cycloadduct bis-1,2,4-triazolo[4,3-a:3’,4’-c]quinoxalines by 1,3-dipolar cycloaddition

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

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

Reattività di diazine benzocondensate asimmetriche nelle reazioni di cicloaddizione 1,3-dipolare con dipoli nitriliminici

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.

Bis-1,2,4-triazolo[4,3-a:3′,4′-c]quinoxalines of pharmaceutical interest from 1,3-dipolar cycloaddition

Abstract Various derivatives of the heterocyclic system 1,12,12a,12b-tetrahydrobis-1,2,4-triazolo[4,3-a:3′,4′-c]quinoxaline of pharmaceutical interest have been obtained by double site- and regio-selective 1,3-dipolar cycloaddition of arylnitrilimines to quinoxalines. No evidence for the formation of mono-adducts was obtained, at variance with literature reports. Specific studies to establish the exact stereochemistry of the bis-cycloadducts were undertaken.

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.

Identificazione e sintesi di nuovi potenziali inibitori di Heat Shock Protein 90

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…

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.

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.

SINTESI ED ATTIVITÀ ANTITUMORALE DI ANALOGHI PENTATOMICI DELLA NORTOPSENTINA

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.

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

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.

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.

Benzothieno-triazolo-pyrimidine: a new class of potential DNA-binders

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…

New annelated thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines, with potent anticancer activity, designed through VLAK protocol

Drug design was performed through the Virtual Lock-and-Key (VLAK) protocol. This in silico approach allowed to select new annelated thienotriazolopyrimidine derivatives, potentially antitumor drugs. Starting from benzothieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine and Pyrido[3',2':4,5]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine core structures, new derivatives of these nuclei were designed and synthesized. Three of them were selected by the Development Therapeutical Program (DTP) of the National Cancer Institute (NCI) for the anticancer screening against a panel of 60 human tumor cell lines. The biological results showed that the new derivatives exhibited an excellent antiproliferative act…

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.

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

Sintesi di Oligopeptidi Pirrolici Isomeri della Distamicina e della Netropsina

AZAINDOLO-FUSED HETEROCYCLES: SYNTHESIS AND ANTITUMOR ACTIVITY

Studi di Docking su Isomeri della Distamicina e della Netropsina

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 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

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.

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

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

SYNTHESIS AND PHOTOBIOLOGICAL ACTIVITY OF PYRROLO-FUSED HETEROCYCLES

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

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

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

Reactivity of asymmetric benzo-condensed diazines with nitrilimine dipoles in the 1,3-dipolar cycloaddition reactions

The reactivity of asymmetric benzo-condensed diazines in the 1,3-dipolar cycloaddition reactions with nitrilimines was investigated. The results demonstrated that, at variance with the symmetric quinoxaline, a certain grade of diastereoselectivity emerged. Moreover in the case of the 5-methylquinoxaline and quinazoline a mono-cycloadduct was obtained.

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

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.

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.

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

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

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.

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

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

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

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.

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-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…

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

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

1,3-Dipolar cycloadditions in the synthesis of annelated diazines: design of new scaffolds for anticancer and antimicrobial agents

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.

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…

Design, synthesis, and biological evaluation of pyridothienotriazolopyrimidine derivatives as new HSP90 inhibitors

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.

Design and Synthesis of 4-Substituted Indolo[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine Derivatives with Antitumor Activity

New derivatives of the indolo[3,2- e][1,2,3]triazolo[1,5- a]pyrimidine system, substituted in the 4 position, were designed as novel antitumor agents because of their theoretical capability to form stable complexes with DNA fragments. The calculated free energies of binding were found in the range -12.76 --> -39.68 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. Compounds, selected on the basis of the docking studies and suitably synthesized, showed antiproliferative activity against each type of tumor cell line investigated, generally in the low micromolar range. The mo…

Glycosidopyrroles. Part 4. 1-β-D-ribofuranosyl-pyrroles and indoles as potential antiviral agents

The preparation of new 1-β-D-ribofuranosylpyrroles of type 8 and a new method of synthesis of 1-β-D-ribofuranosylindoles of type 10, according to the scheme, is reported. All these new derivatives showed promising chemical and physical analogies with bioactive molecules but did not show any antiviral activity againstHIV1.

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

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

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.

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.