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

Chongwen Bi; Cheng Ye; Yinghong Li; Wuli Zhao; Rongguang Shao; Danqing Song

doi:10.1016/j.apsb.2016.03.004

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

Acta Pharm Sin B. 2016 May;6(3):222-8. doi: 10.1016/j.apsb.2016.03.004. Epub 2016 Apr 14.

Authors

Chongwen Bi¹, Cheng Ye², Yinghong Li², Wuli Zhao², Rongguang Shao², Danqing Song²

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China; Tianjin Medical University General Hospital, Tianjin 300052, China.
² Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.

Abstract

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.

Keywords: Anticancer; Drug resistance; Sophoridinic derivatives; Structure–activity relationship; Synthesis.