Synthesis and Biological Evaluation of Novel Homocamptothecins Conjugating with Dihydropyrimidine Derivatives as Potent Topoisomerase I Inhibitors

✍ Scribed by Lingjian Zhu; Pengfei Cheng; Ning Lei; Jianzhong Yao; Chunquan Sheng; Chunlin Zhuang; Wei Guo; Wenfeng Liu; Yongqiang Zhang; Guoqiang Dong; Shengzhang Wang; Zhenyuan Miao; Wannian Zhang

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 334 KB
• Volume: 344
• Category: Article
• ISSN: 0365-6233
• DOI: 10.1002/ardp.201000402

✦ Synopsis

Abstract

Homocamptothecin (hCPT) is a camptothecin (CPT) homologue with the insertion of a methylene (CH~2~) spacer between the alcohol moiety and carbonyl group of the classical six‐membered α‐hydroxylactone ring. This modification provides higher lactone stability and did not impair its activity against topoisomerase I (Topo I), but rather appears to improve it compared to CPT. In an attempt to improve the antitumor activity of homocamptothecins, a series of novel hCPT derivatives conjugating with dihydropyrimidine (DHPM) derivatives was designed and synthesized based on a synthetic route which couples 7‐formylhomocamptothecin with different dihydropyrimidine derivates. Most of the synthesized compounds exhibited good antiproliferative activity on tumor cell lines A549, MDA‐MB‐435 and HCT116. Furthermore, this class of compounds showed superior Topo I inhibition activity comparable to or higher than CPT.