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Ippolito Antonini - One of the best experts on this subject based on the ideXlab platform.
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rational design synthesis and biological evaluation of bis pyrimido 5 6 1 de Acridines and bis pyrazolo 3 4 5 kl acridine 5 carboxamides as new anticancer agents
Journal of Medicinal Chemistry, 2004Co-Authors: Ippolito Antonini, Paolo Polucci, Amelia Magnano, Silvia Sparapani, S MartelliAbstract:The good results obtained with pyrimido[5,6,1-de]Acridines 7 and with pyrazolo[3,4,5-kl]acridinecarboxamides 8 prompted us to the synthesis of two new series of bis acridine derivatives: the bis(pyrimidoAcridines) 5 and the bis(pyrazoloacridinecarboxamides) 6. Compounds 5 can be regarded also as cyclized derivatives of bis(acridine-4-carboxamides) 3 and compounds 6 as cyclized derivatives of bis(acridine-4-carboxamides) 4. The noncovalent DNA-binding properties of these compounds have been examined using fluorometric techniques. The results indicate that (i) the target compounds are excellent DNA ligands; (ii) the bis derivatives 5 and 6 are more DNA-affinic than corresponding monomers 7 and 8; (iii) the new bis 5 and 6 result always less efficient in binding than related bis(acridine-4-carboxamides) 3 and 4; and (iv) in both series 5 and 6 a clear, remarkable in some cases, preference for binding to AT rich duplexes can be noted. In vitro cytotoxic potency of these derivatives toward the human colon ade...
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DNA-binding antitumor agents: from pyrimido[5,6,1-de]Acridines to other intriguing classes of acridine derivatives.
Current Medicinal Chemistry, 2002Co-Authors: Ippolito AntoniniAbstract:: In the field of antitumor DNA-binding agents, the class of acridine derivatives play an important role either as number of compounds or as importance of their anticancer properties. We have synthesized a number of acridine derivatives as potential antitumor drugs, in which the chromophore is fully or partially constituted by acridine or by 9-acridone ring systems: from the pyrimido[5,6,1-de]Acridines, to the pyrimido[4,5,6-kl]Acridines, the bis(amine-functionalized) 9-acridone-4-carboxamides, the bis(amine-functionalized) acridine-4-carboxamides, and the pyrazolo[3,4,5-kl]acridine-5-carboxamides. In the present revue we will describe the rational design, the synthesis, and the salient biological characteristics of these classes of acridine derivatives.
Malcolm F. G. Stevens - One of the best experts on this subject based on the ideXlab platform.
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antitumour polycyclic Acridines part 10 synthesis of penta and hexa cyclic heteroaromatic systems by radical cyclisations of substituted 9 anilinoAcridines
Journal of The Chemical Society-perkin Transactions 1, 2001Co-Authors: Michael J Ellis, Malcolm F. G. StevensAbstract:9-AnilinoAcridines substituted with a bromine atom in the 2-position of the anilino group or the 1-position of the acridine moiety can be cyclised with tributyltin hydride–AIBN to penta- or hexacyclic Acridines. Of the polycyclic systems 13,14-dihydropyrrolo[3′,2′,1′:8,1]quino[4,3,2-kl]acridine 14a is the most potent cytotoxic agent displaying a mean GI50 concentration against a panel of 60 human tumour cell lines of 0.06 μM.
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Antitumour polycyclic Acridines. Part 4. Physico-chemical studies on the interactions between DNA and novel tetracyclic acridine derivatives.
Anti-cancer Drug Design, 1998Co-Authors: E. Gimenez-arnau, Sotiris Missailidis, Malcolm F. G. StevensAbstract:The noncovalent interactions between a series of new polycyclic acridine derivatives (1-5) and salmon testes DNA have been studied using several physicochemical techniques. These include spectrophotometric analysis, fluorescence quenching, thermal denaturation, and circular and linear dichroism. In order to compare the extent of the DNA binding by compounds 1-5 in their neutral and cationic forms, all experiments have been conducted at pH 7.4 and at pH 5.0. Other polynucleotides, including [Poly(dA-dT)] 2 and [Poly(dG-dC)] 2 , were used in order to study the DNA base-pair binding specificity of these novel annelated acridine derivatives. The results indicate that the new polycyclic Acridines display the following properties: (i) they are strong DNA-binding ligands with affinities 10- to 400-fold greater than that of acridine, 3- to 100-fold greater than that of m-AMSA (6) and 1- to 23-fold greater than that of proflavine at physiological pH (7.4); (ii) they have stronger DNA-binding activity at pH 5.0 as a result of the N-protonation of the aromatic chromophore; (iii) they bind more selectively to [Poly(dA-dT)] 2 polynucleotide than to [Poly(dG-dC)] 2 polynucleotide; (iv) within the series compound 3 binds to DNA less than compounds 1, 2, 4 and 5 at both pH values studied; and (v) the polycyclic Acridines form a molecular complex with DNA undergoing intercalation inside the duplex macromolecule, as shown by linear and circular dichroism. Nevertheless, circular dichroism studies reveal alternative binding modes at low DNA:drug ratios.
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Antitumour polycyclic Acridines. Part 3.1 A two-step conversion of 9-azidoacridine to 7H-pyrido[4,3,2-kl]Acridines by Graebe–Ullmann thermolysis of substituted 9-(1,2,3-triazol-1-yl)Acridines
Journal of the Chemical Society Perkin Transactions 1, 1998Co-Authors: Damien J. Hagan, David Chan, Carl H. Schwalbe, Malcolm F. G. StevensAbstract:9-Azidoacridine 5 reacted with a series of alkynes to form mixtures of regioisomeric 9-(4- and 5-substituted-1,2,3-triazol-1-yl)Acridines 6, except for the reaction with trimethylsilylacetylene which gave a single regioisomer. Structural assignments have been confirmed by 1H NMR and NOE experiments and the X-ray structure of 9-(4-butyl-1,2,3-triazol-1-yl)acridine 6a corroborates the positioning of the butyl group and shows that the plane of the triazole ring intersects that of the acridine moiety by 65.97(5)° in the crystal structure. Graebe–Ullmann fragmentation of the triazolylAcridines was monitored by differential scanning calorimetry and preparative thermolytic conversion to 2- or 3-substituted 7H-pyrido[4,3,2-kl]Acridines 8 was performed in hot diphenyl ether. Whereas 9-[4-(3-chloropropyl)-1,2,3-triazol-1-yl]acridine 11 cyclised to 3-(3-chloropropyl)-7H-pyrido[4,3,2-kl]acridine 13, the isomeric triazole 12 afforded the pentacyclic salt 1H,8H-2,3-dihydroindolizino[7,6,5-kl]acridinium chloride 15.
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antitumour polycyclic Acridines part 5 1 synthesis of 7h pyrido 4 3 2 kl Acridines with exploitable functionality in the pyridine ring
Journal of The Chemical Society-perkin Transactions 1, 1998Co-Authors: Markus Julino, Malcolm F. G. StevensAbstract:Two series of new 9-(1,2,3-triazol-1-yl)Acridines 8 and 11 have been synthesised by base catalysed cyclisation reaction of 9-azidoacridine 5 with either 1,3-dicarbonyl compounds or activated acetonitriles. Ring formation occurred in a regiospecific manner indicating a stepwise ionic reaction sequence. The combination of activating base and solvent, as well as the solubility of the products, are crucial for achieving acceptable yields. Several of the 9-(1,2,3-triazol-1-yl)Acridines have been converted to fluorescent 7H-pyrido[4,3,2-kl]Acridines 14 by Graebe–Ullmann nitrogen-expulsion degradations employing boiling diphenyl ether as the thermolytic medium. In one case, the thermolysis of 9-[4-methoxycarbonyl-5-(4-chlorobutyl)-1,2,3-triazol-1-yl]acridine 16, the chlorobutyl side-chain participated in an additional intramolecular cyclisation step leading to the pentacyclic quinolizino[2,3,4-kl]acridine 18.
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antitumour polycyclic Acridines part 1 synthesis of7h pyrido and 8h quino 4 3 2 kl Acridinesby graebe ullmann thermolysis of 9 1 2 3 triazol 1 yl Acridines application of differential scanning calorimetry to predict optimumcyclisation conditions
Journal of The Chemical Society-perkin Transactions 1, 1997Co-Authors: Damien J. Hagan, Carl H. Schwalbe, E Gimenezarnau, Malcolm F. G. StevensAbstract:The thermal decomposition of a series of Acridines substituted in the 9-position with 1,2,3-triazol-1-yl, benzotriazol-1-yl and naphthotriazol-1-yl groups has been studied by differential scanning calorimetry. Whereas the monocyclic triazole 7a shows a discrete melting endotherm followed by a decomposition exotherm corresponding to formation of the 7H-pyrido[4,3,2-kl]acridine 8, in the benzotriazoles 10a–e and naphthotriazole 10f these processes coincide with a single sharp exothermic transition attributed to cyclisation to polycyclic Acridines 11a–f, respectively. The optimum conditions for the preparative scale synthesis of polycyclic Acridines from triazole precursors utilised boiling diphenyl ether as the decomposition medium. A benzotriazol-1-ylacridine 10e substituted in the peri position with a methyl group behaved anomalously: as well as affording the expected 8H-quino[4,3,2-kl]acridine 11e, cyclisation also led to radical mediated loss of the methyl group to form the unsubstituted 8H-quino[4,3,2-kl]acridine 11a and H-abstraction from the methyl group leading to the benzoazepinoacridine 12. Radical cyclisation of 9-(2-iodoanilino)acridine 16 also gave 8H-quino[4,3,2-kl]acridine 11a. The crystal structure of 11a confirms the 8H tautomer arrangement with intermolecular N8–H · · · N13 hydrogen bonding and exhibits a polycyclic system that is planar with rms deviation 0.044 A.
Upendra Sharma - One of the best experts on this subject based on the ideXlab platform.
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metal free synthesis of 2 substituted 3 2 hydroxyaryl quinolines and 4 2 hydroxyaryl Acridines via benzyne chemistry
Journal of Organic Chemistry, 2017Co-Authors: Ankit Kumar Dhiman, Rakesh Kumar, Upendra SharmaAbstract:A metal-free approach for the synthesis of 3-aryl-2-substituted quinolines and 4-arylAcridines has been developed via the 1,3-dipolar cycloaddition reactions of arynes with N-oxides. Reactions of various 2-substitued quinoline N-oxides with ortho-(trimethylsilyl)aryltriflates in the presence of KF gave 3-(2-hydroxyaryl)quinoline derivatives in good yields. Acridine N-oxides also reacted with arynes to furnish 4-(2-hydroxyaryl)Acridines, albeit in moderate yields.
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Metal-Free Synthesis of 2‑Substituted 3‑(2-Hydroxyaryl)quinolines and 4‑(2-Hydroxyaryl)Acridines via Benzyne Chemistry
2017Co-Authors: Ankit Kumar Dhiman, Rakesh Kumar, Upendra SharmaAbstract:A metal-free approach for the synthesis of 3-aryl-2-substituted quinolines and 4-arylAcridines has been developed via the 1,3-dipolar cycloaddition reactions of arynes with N-oxides. Reactions of various 2-substitued quinoline N-oxides with ortho-(trimethylsilyl)aryltriflates in the presence of KF gave 3-(2-hydroxyaryl)quinoline derivatives in good yields. Acridine N-oxides also reacted with arynes to furnish 4-(2-hydroxyaryl)Acridines, albeit in moderate yields
S Martelli - One of the best experts on this subject based on the ideXlab platform.
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rational design synthesis and biological evaluation of bis pyrimido 5 6 1 de Acridines and bis pyrazolo 3 4 5 kl acridine 5 carboxamides as new anticancer agents
Journal of Medicinal Chemistry, 2004Co-Authors: Ippolito Antonini, Paolo Polucci, Amelia Magnano, Silvia Sparapani, S MartelliAbstract:The good results obtained with pyrimido[5,6,1-de]Acridines 7 and with pyrazolo[3,4,5-kl]acridinecarboxamides 8 prompted us to the synthesis of two new series of bis acridine derivatives: the bis(pyrimidoAcridines) 5 and the bis(pyrazoloacridinecarboxamides) 6. Compounds 5 can be regarded also as cyclized derivatives of bis(acridine-4-carboxamides) 3 and compounds 6 as cyclized derivatives of bis(acridine-4-carboxamides) 4. The noncovalent DNA-binding properties of these compounds have been examined using fluorometric techniques. The results indicate that (i) the target compounds are excellent DNA ligands; (ii) the bis derivatives 5 and 6 are more DNA-affinic than corresponding monomers 7 and 8; (iii) the new bis 5 and 6 result always less efficient in binding than related bis(acridine-4-carboxamides) 3 and 4; and (iv) in both series 5 and 6 a clear, remarkable in some cases, preference for binding to AT rich duplexes can be noted. In vitro cytotoxic potency of these derivatives toward the human colon ade...
William A. Denny - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and cytotoxicity of potential anticancer derivatives of pyrazolo[3,4,5-kl]acridine and indolo[2,3-a]acridine
Tetrahedron, 2002Co-Authors: Junjie Chen, Leslie W. Deady, William A. DennyAbstract:Abstract Pyrazolo[3,4,5- kl ]Acridines were prepared by reaction of ethyl 1,9-dioxo-1,2,3,4,9,10-hexahydroacridine-4-carboxylate ( 4 ) with hydrazine and its methyl and 2-(dimethylamino)ethyl derivatives, followed by aromatization of the intermediate products with 1,4-benzoquinone. Conversion of the ester function to a carboxamide was also carried out and N -(2-(dimethylamino)ethyl)-1-(2-(dimethylamino)ethyl)-1,2-dihydropyrazolo[3,4,5- kl ]acridine-5-carboxamide ( 13c ) was appreciably cytotoxic in a panel of cell lines. Reaction of 4 with 4-methoxyphenylhydrazine gave instead a novel indolo[2,3- a ]acridine derivative.
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The genetic toxicology of Acridines.
Mutation research, 1991Co-Authors: Lynnette R. Ferguson, William A. DennyAbstract:Acridine and its derivatives are planar polycyclic aromatic molecules which bind tightly but reversibly to DNA by intercalation, but do not usually covalently interact with it. Acridines have a broad spectrum of biological activities, and a number of derivatives are widely used as antibacterial, antiprotozoal and anticancer drugs. Simple Acridines show activity as frameshift mutagens, especially in bacteriophage and bacterial assays, by virtue of their intercalative DNA-binding ability. Acridines bearing additional fused aromatic rings (benzAcridines) show little activity as frameshift mutagens, but interact covalently with DNA following metabolic activation (forming predominantly base-pair substitution mutations). Compounds where the acridine acts as a carrier to target alkylating agents to DNA (e.g. the ICR compounds) cause predominantly frameshift as well as base-pair substitution mutations in both bacterial and mammalian cells. NitroAcridines may act as simple Acridines or (following nitro group reduction) as alkylating agents, depending upon the position of the nitro group. Acridine-based topoisomerase II inhibitors, although frameshift mutagens in bacteria and bacteriophage systems, are primarily chromosomal mutagens in mammalian cells. These mutagenic activities are important, since the compounds have considerable potential as clinical antitumour drugs. Although evidence suggests that simple Acridines are not animal or human carcinogens, a number of the derived compounds are highly active in this capacity.
