Design, synthesis and biological evaluation of novel asperphenamate derivatives

• Published in: European journal of medicinal chemistry 2016-03, Vol.110, p.76-86
• Main Authors: Liu, Qingyin, Li, Wei, Sheng, Lei, Zou, Chunyang, Sun, Hongxin, Zhang, Chunfeng, Liu, Yang, Shi, Jiyue, Ma, Enlong, Yuan, Lei
• Format: Article
• Language: English
• Subjects: Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Asperphenamate; Autophagy - drug effects; Cell Line, Tumor; Dipeptide analog; Drug Design; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Inducing autophagy; MCF-7 Cells; Neoplasms - drug therapy; Neoplasms - pathology; Phenylalanine - analogs & derivatives; Phenylalanine - chemical synthesis; Phenylalanine - chemistry; Phenylalanine - pharmacology; Structure-Activity Relationship; Synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.01.020

A series of novel asperphenamate derivatives were designed and synthesized, including series I (the A-phenyl group replaced with various aromatic heterocycles) and series II (the acyl group substituted by sulfonyl group). All compounds have been screened for their antiproliferative activity in vitro against MCF-7, HeLa, and BEL-7402 cell lines by the standard MTT method. Structure–activity relationship studies displayed the heterocycle type played an important role in activity. Six-membered ring derivatives displayed more potency than five-membered ring and the sulfonyl group in A-ring region made an important contribution to activity. Among all derivatives, tosyl derivative 8c exhibited the greatest potency in three human cancer cell lines. Especially in MCF-7 cells, the cellular potency of 8c was approximately 3.0-fold more potent than that of cisplatin. Firstly, the mechanism of cell death induced by 8c in MCF-7 cells was investigated. The results showed that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest. Further studies indicated that 8c might induce autophagic cell death in HeLa and BEL-7402 cell lines. [Display omitted] •Two series of asphenamate derivatives were designed and synthesized.•The target compounds showed potent antitumor activity.•The cellular potency of 8c against MCF-7 and BEL-7402 cell lines was more potent than that of cisplatin.•8c was selected to investigate the antitumor mechanisms.•8c induced cell death in MCF-7, HeLa and BEL-7402 cell lines by autophagy instead of apoptosis or cell cycle arrest.