二氮杂和三氮杂并四苯：靶向拓扑异构酶的强效药物，对人肿瘤异种移植模型MDA-MB-435具有卓越的抗肿瘤活性。

Diaza- and triazachrysenes: potent topoisomerase-targeting agents with exceptional antitumor activity against the human tumor xenograft, MDA-MB-435.

作者信息

Ruchelman Alexander L, Singh Sudhir K, Wu Xiaohua, Ray Abhijit, Yang Jin-Ming, Li Tsai-Kun, Liu Angela, Liu Leroy F, LaVoie Edmond J

机构信息

Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.

出版信息

Bioorg Med Chem Lett. 2002 Nov 18;12(22):3333-6. doi: 10.1016/s0960-894x(02)00737-0.

DOI:10.1016/s0960-894x(02)00737-0

PMID:12392745

Abstract

Several 5,12-diazachrysen-6-ones and 5,6,11-triazachrysen-12-ones were synthesized with varied substituents at the 5- or 11-position, respectively. Each compound was evaluated for its potential to stabilize the cleavable complex formed with TOP1 and DNA. Two analogues with very potent TOP1-targeting activity, 3a and 4a, exhibited cytotoxic activity with IC(50) values at or below 2nM against RPMI8402. Compound 3a was active in vivo by either ip or po administration in the human tumor xenograft athymic nude mice model.

摘要

分别合成了几种在5-位或11-位带有不同取代基的5,12-二氮杂并四苯-6-酮和5,6,11-三氮杂并四苯-12-酮。评估了每种化合物稳定由TOP1和DNA形成的可裂解复合物的潜力。两种具有非常强的TOP1靶向活性的类似物3a和4a，对RPMI8402表现出细胞毒性活性，IC(50)值等于或低于2nM。化合物3a在人肿瘤异种移植无胸腺裸鼠模型中通过腹腔注射或口服给药在体内具有活性。