Synthesis and biological evaluation of 12-N-p-chlorobenzyl sophoridinol derivatives as a novel family of anticancer agents

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• 作者：Chongwen Bi^a ; ^b ; Cheng Ye^a ; Yinghong Li^a ; Wuli Zhao^a ; Rongguang Shao^a ; Danqing Song^a ; ^{songdanqingsdq@hotmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Sophoridinic derivatives ; Synthesis ; Structure&ndash ; activity &#xA0 ; relationship ; Anticancer ; Drug resistance
• 刊名：Acta Pharmaceutica Sinica B
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：6
• 期：3
• 页码：222-228
• 全文大小：1009 K

文摘

Taking 12-N-p-chlorobenzyl sophoridinol 2 as a lead, a series of novel sophoridinic derivatives with various 3′-substituents at the 11–side chain were synthesized and evaluated for their anticancer activity from sophoridine (1), a natural antitumor medicine. Among them, the sophoridinic ketones 5a–b, alkenes 7a–b and sophoridinic amines 14a–b displayed reasonable antiproliferative activity with IC₅₀ values ranging from 3.8 to 5.4 μmol/L. Especially, compounds 5a and 7b exhibited an equipotency in both adriamycin (AMD)-susceptible and resistant MCF-7 breast carcinoma cells, indicating a different mechanism from AMD. The primary mechanism of action of 5a was to arrest the cell cycle at the G0/G1 phase, consistent with that of parent compound 1. Thus, we consider 12-chlorobenzyl sophoridinic derivatives with a tricyclic scaffold to be a new class of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.