School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
Eur J Med Chem. 2010 Jul;45(7):2726-32. doi: 10.1016/j.ejmech.2010.02.051. Epub 2010 Mar 1.
The homocamptothecin (hCPT) represents a new class of topoisomerase inhibitor which combines enhanced plasma stability and strong antitumor activity. Fluorine imparts desirable characteristics to drugs by modulating both the pharmacokinetics and pharmacodynamic properties of a drug. Therefore, in an attempt to improve the antitumor activity of homocamptothecins, seven new 7-trifluoromethylated homocamptothecin derivatives were prepared by proline-catalyzed Friedlander annulation. The antitumor activity in vitro and in vivo on cancer cell lines, and inhibitory properties of topoisomerase I-mediated DNA cleavage of compounds 6c and 8b were evaluated. Several of these trifluoromethylated hCPT derivatives (such as 6a, 6b and 6c) possessed higher in vitro antitumor activity than topotecan (TPT). Especially, the compound 6c showed effective in vivo antitumor activity comparable to that of TPT.
霍夫曼重排（homocamptothecin，hCPT）是一种新型拓扑异构酶抑制剂，具有增强的血浆稳定性和强大的抗肿瘤活性。氟通过调节药物的药代动力学和药效学特性，为药物赋予理想的特性。因此，为了提高霍夫曼重排物的抗肿瘤活性，我们通过脯氨酸催化的 Friedlander 环合反应，制备了 7 种新型的 7-三氟甲基霍夫曼重排物衍生物。评估了化合物 6c 和 8b 在体外和体内对癌细胞系的抗肿瘤活性以及对拓扑异构酶 I 介导的 DNA 断裂的抑制特性。这些三氟甲基化 hCPT 衍生物中的几种（如 6a、6b 和 6c）具有比拓扑替康（topotecan，TPT）更高的体外抗肿瘤活性。特别是，化合物 6c 表现出与 TPT 相当的有效的体内抗肿瘤活性。
