- Synthesis and antiproliferative activity of some variously substituted acridine and azacridine derivatives
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A group of 9-substituted acridine and azacridine derivatives (m-AMSA analogues) were synthesised following classical procedures as potential antitumour agents with inhibitory effects on DNA topoisomerase II. Some were found to have noticeable cytotoxicity against human HL-60 and HeLa cells grown in culture. Their non-covalent interactions with calf thymus DNA have been studied using fluorescence quenching. We evaluated DNA damage produced by the tested compounds by means of DNA filter elution and protein precipitation techniques. Catalytic studies carried out with purified topoisomerase confirmed these agents as antitopoisomerase inhibitors. Chemotherapy of solid-tumour-bearing mice with tested compounds allowed an aza-analogue (compound IIIb), as potent as m-AMSA but less toxic towards the host, to be recognised. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Ferlin, Maria Grazia,Marzano, Cristina,Chiarelotto, Gianfranco,Baccichetti, Francarosa,Bordin, Franco
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p. 827 - 837
(2007/10/03)
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- Pyrrolo-quinoline derivatives as potential antineoplastic drugs
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Some novel pyrrolo-quinoline derivatives have been synthesized as potential antineoplastic agents. They contain an angular aromatic tricyclic or tetracyclic system, to which the methanesulfon-anisidide side chain typical of amsacrine as such, or lacking the m-methoxy substituent, is connected. A methyl group can be present at position 7 of the pyrrolo-quinoline ring. The novel compounds exhibit interesting cell growth inhibitory properties when tested against the NCI panel of cell lines, in particular those obtained from solid tumors like CNS-, melanoma- and prostate-derived cells. The mechanism of cytotoxic action does not seem to be related to topoisomerase II poisoning ability. Most active proved to be compound 4a, which lacks both methyl and methoxy substituents, followed by 5a, having the methoxy group only. Biological activity is less pronounced in the tetracyclic family of derivatives 6 and 7. Copyright (C) 2000 Elsevier Science Ltd.
- Ferlin,Gatto,Chiarelotto,Palumbo
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p. 1415 - 1422
(2007/10/03)
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- Anticancer anilinoacridines. A process synthesis of the disubstituted amsacrine analog CI-921
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An improved process for the synthesis of bulk quantities of the clinical amsacrine analog CI-921 is reported. Described also are detailed analytical and spectroscopic data for this agent.
- Brennan,Colbry,Leeds,Leja,Priebe,Reily,Showalter,Uhlendorf,Atwell,Denny
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p. 1469 - 1476
(2007/10/02)
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- Potential Antitumor Agents. 48. 3'-Dimethylamino Derivatives of Amsacrine: Redox Chemistry and in Vivo Tumor Activity
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Structure-activity relationships for a series of acridine-substituted 3'-N(CH3)2 derivatives of the clinical antileukemic drug amsacrine (1) are reported.The parent (unsubstituted) compound 3 has activity against the Lewis lung solid tumor that is superior to amsacrine(1), the new clinical amsacrine analogue 4, and the recently developed 3'-NHCH3 derivative 2.Although the compounds generally bind less well to DNA and are less dose potent in vivo than either their amsacrine (3'-OCH3) or 3'-NHCH3 analogues, they show very high levels of antitumor activity, with the 4-OCH3 derivative capable of effecting 100percent cures of the Lewis lung solid tumor.The broad structure-activity relationships for acridine substitution more closely resemble those of the amsacrine than the 3'-NHCH3 series, with 4-substituted and 4,5-disubstituted compounds showing the highest activity.
- Atwell, Graham J.,Rewcastle, Gordon W.,Baguley, Bruce C.,Denny, William A.
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p. 652 - 658
(2007/10/02)
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- Kinetics and Mechanism of Thiolytic Cleavage of the Antitumor Compound 4'-methanesulfon-m-anisidide
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The thiolysis of 4'-methanesulfon-m-anisidide (m-AMSA) has been studied in buffer solutions of L-cysteine, glutathione, N-acetylcysteine, 2-mercaptoethanol, and cysteamine at various pH values.The thiolysis is sensitive to general-acid catalysis.Both free and protonated forms of m-AMSA have been found to be reactive for thiolysis.The Broensted-type correlation of thiol basicity to the nucleophilic rate constants with the protonated m-AMSA (m-AMSA+H) has a slope, βnuc of 0.74 +/- 0.07 which indicates that probably the expulsion of the leavinggroup is the rate-determining step.The rate constants for general-acid-catalyzed thiolytic cleavage of m-AMSA+H reveal an insensitiveness to the acidity of catalysts.The general-acid-catalyzed rate constants for thiolysis of the free base of m-AMSA have been found to have quite high sensitivities to the pKa of catalysts (α = 0.57 +/- 0.07) which has been interpreted by assuming a concerted type of mechanism for thiolysis.The various ionic forms of amino thiols are acting as nucleophiles as well as general-acid catalysts, depending upon the pH range of the reaction and the microscopic ionization constants of the thiols.The unionized thiol groups of most of the catalysts are acting as general acids except for cysteamine where the protonated amino group is also acting as a general-acid catalyst.A high nucleophilic rate constant for cysteamine with m-AMSA (free base) compared with those for other nucleophiles of similar basicity has been attributed to its probable ability of acting as an intramolecular general-acid catalyst.The thiolytic cleavage of m-AMSA+H is nearly 103 times faster than that of m-AMSA (free base) while the ratios for general-acid-catalyzed rate constants for m-AMSA+H and m-AMSA (free base) vary from 20 to 300 depending upon the pKa of the catalysts.The bimolecular nucleophilic rate constant (with m-AMSA+H) as well as the general-acid-catalyzed rate constant (with m-AMSA free base) for glutathione is found to be positively deviated from Broensted plots which seem as if they fall on a separate Broensted plot of essentially the same slope but with a different intercept.
- Khan, Niyaz M.,Malspeis, L.
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p. 2731 - 2740
(2007/10/02)
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- Multi-step process for the production of methanesulfon-m-anisidide, 4'-(9-acridinylamino)-
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A multi-step method of producing the compound methanesulfon-m-anisidide, 4''-(9-acridinylamino)-, acetate (VII), which may be in free base form and designated NSC 249992, also known as AMSA. This compound is produced by an elegant process from a starting material, 4-butyrylamino-3-methoxy-nitrobenzene, which is later transformed to methanesulfon-m-anisidide, 4''-amino- (IV) and is coupled or joined to 9-chloro-acridine, producing the chloride salt which is later converted to the acetate.
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