Synthesis,cytotoxic activity,and DNA binding properties of antitumor cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine cinnamoyl esters |
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| Authors: | Quyên Do Wen Tian Rodrigue Yougnia Thomas Gaslonde Bruno Pfeiffer Alain Pierré Stéphane Léonce Laurence Kraus-Berthier Marie-Hélène David-Cordonnier Sabine Depauw Amélie Lansiaux Romain Mazinghien Michel Koch François Tillequin Sylvie Michel Hanh Dufat |
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| Affiliation: | 1. Laboratoire de Pharmacognosie de l’Université Paris Descartes, U.M.R./C.N.R.S. No. 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l’Observatoire, 75006 Paris, France;2. Institut de Recherches Servier, Division Recherche Cancérologie, 125 Chemin de Ronde, 78290 Croissy sur Seine, France;3. INSERM U-837-Centre de Recherches Jean-Pierre Aubert (Team 4 Molecular and Cellular Targeting for Cancer Treatment) and IMPRT-IFR114, IRCL, 59045 Lille Cedex, France;4. Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, 59045 Lille Cedex, France |
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| Abstract: | Monocinnamoyl esters at position 2 of (±)-cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one and their acetyl derivatives at position 1 were prepared as stabilized analogues of the anticancer alkylating agent S23906-1. Monocinnamoyl esters at position 2 were slower DNA alkylators than the reference 2-monoacetate. Mixed esters bearing an acetyl ester group at position 1 and a cinnamoyl ester group at position 2 alkylated DNA slower than S23906-1. A strong correlation was observed between cytotoxicity and DNA alkylation kinetics, with slower alkylators displaying more potent antiproliferative activities. The most cytotoxic compounds proved to be significantly active in vivo against murine C-38 adenocarcinoma implanted in mice, but less potent than S23906-1. |
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