抗肿瘤顺式-1,2-二羟基-1,2-二氢苯并[b]吖啶肉桂酸酯的合成、细胞毒性活性及DNA结合特性

Synthesis, cytotoxic activity, and DNA binding properties of antitumor cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine cinnamoyl esters.

作者信息

Do Quyên, Tian Wen, Yougnia Rodrigue, Gaslonde Thomas, Pfeiffer Bruno, Pierré Alain, Léonce Stéphane, Kraus-Berthier Laurence, David-Cordonnier Marie-Hélène, Depauw Sabine, Lansiaux Amélie, Mazinghien Romain, Koch Michel, Tillequin François, Michel Sylvie, Dufat Hanh

机构信息

Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Pharmacognosie de l'Université Paris Descartes, UMR/CNRS No 8638, Paris, France.

出版信息

Bioorg Med Chem. 2009 Mar 1;17(5):1918-27. doi: 10.1016/j.bmc.2009.01.062. Epub 2009 Jan 31.

DOI:10.1016/j.bmc.2009.01.062

PMID:19217791

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.

摘要

制备了(±)-顺式-1,2-二羟基-6-甲氧基-3,3,14-三甲基-1,2,3,14-四氢-7H-苯并[b]吡喃并[3,2-h]吖啶-7-酮2位的单肉桂酰酯及其1位的乙酰衍生物，作为抗癌烷化剂S23906-1的稳定类似物。2位的单肉桂酰酯作为DNA烷化剂比参考的2-单乙酸酯慢。1位带有乙酰酯基团且2位带有肉桂酰酯基团的混合酯使DNA烷基化的速度比S23906-1慢。在细胞毒性和DNA烷基化动力学之间观察到强烈的相关性，烷基化较慢的化合物表现出更强的抗增殖活性。最具细胞毒性的化合物在体内对植入小鼠的鼠C-38腺癌具有显著活性，但效力低于S23906-1。