Sugimori M, Ejima A, Ohsuki S, Uoto K, Mitsui I, Kawato Y, Hirota Y, Sato K, Terasawa H
Tokyo R&D Center, Daiichi Pharmaceutical Company, Ltd., 16-13, Kitakasai 1-Chome, Edogawa-ku, Tokyo 134, Japan.
J Med Chem. 1998 Jun 18;41(13):2308-18. doi: 10.1021/jm970765q.
Nineteen ring A- and F-modified hexacyclic analogues of camptothecin were synthesized by Friedländer condensation of appropriately substituted bicyclic amino ketones with tricyclic ketone and were evaluated for cytotoxicity and topoisomerase I inhibitory activity. Seventeen of the compounds showed cytotoxic effects comparable or superior to those of 7-ethyl-10-hydroxycamptothecin (SN-38) against mouse leukemia P388 and human tumor cell lines HOC-21 and QG-56. Introduction of a compact and inductively electron-withdrawing substituent such as a hydroxy, methoxy, chloro, or fluoro group into position 5 of ring A of the hexacyclic compound remarkably increased the antitumor activity. The potency of topoisomerase I inhibition of these compounds showed good correlation with their cytotoxicity. Among them, the 4-methyl-5-fluoro hexacyclic compound was the most potent of all and was 10 times as active as SN-38 in in vitro antitumor activity.
通过适当取代的双环氨基酮与三环酮的Friedländer缩合反应，合成了19种喜树碱的A环和F环修饰的六环类似物，并对其细胞毒性和拓扑异构酶I抑制活性进行了评估。其中17种化合物对小鼠白血病P388以及人肿瘤细胞系HOC-21和QG-56显示出与7-乙基-10-羟基喜树碱（SN-38）相当或更强的细胞毒性作用。在六环化合物的A环5位引入紧凑的吸电子取代基，如羟基、甲氧基、氯或氟基团，可显著提高其抗肿瘤活性。这些化合物对拓扑异构酶I的抑制效力与其细胞毒性显示出良好的相关性。其中，4-甲基-5-氟六环化合物活性最强，其体外抗肿瘤活性是SN-38的10倍。
