Pons Valérie, Beaumont Stéphane, Tran Huu Dau Marie Elise, Iorga Bogdan I, Dodd Robert H
Institut de Chimie des Substances Naturelles, UPR 2301, Campus de Recherche de Gif, Centre National de la Recherche Scientifique, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
ACS Med Chem Lett. 2011 Jun 5;2(8):565-70. doi: 10.1021/ml200024y. eCollection 2011 Aug 11.
Two rigid analogues of 5-ethylindolobenzazepinone 4, a potent cytotoxic agent and inhibitor of tubulin polymerization, were prepared. The first was the indane derivative 5, in which the ethyl group is attached to the benzo moiety. The second was the pyrrolidine analogue 6, in which the ethyl chain was bound to the lactam nitrogen. While both compounds were considerably less active inhibitors of KB cell growth as compared to 4, inhibition of tubulin polymerization was only moderately reduced. Tubulin docking studies indicated that the aR and aS atropoisomers of 5 and 6 occupy different binding pockets at the colchicine binding site. Conversely, both aS-5 and aS-6 occupy the same binding pocket as aSS-4 but do not benefit from the favorable hydrophobic interactions provided by the C5 alkyl group of 4, thus possibly explaining their lower activities.
制备了5-乙基吲哚苯并氮杂䓬酮4的两种刚性类似物，5-乙基吲哚苯并氮杂䓬酮4是一种有效的细胞毒性剂和微管蛋白聚合抑制剂。第一种是茚满衍生物5，其中乙基连接在苯并部分上。第二种是吡咯烷类似物6，其中乙基链连接在内酰胺氮上。与4相比，这两种化合物对KB细胞生长的抑制活性都显著降低，但微管蛋白聚合抑制作用仅适度降低。微管蛋白对接研究表明，5和6的aR和aS阻转异构体在秋水仙碱结合位点占据不同的结合口袋。相反，aS-5和aS-6与aSS-4占据相同的结合口袋，但没有受益于4的C5烷基提供的有利疏水相互作用，因此可能解释了它们较低的活性。
