Design, Synthesis and Antiproliferative Activity of 2-Acetamidothiazole-5- carboxamide Derivatives

Wukun      Liu; Jinpei      Zhou; Yu      Zheng; Fan      Qi; Huibin      Zhang; Hai      Qian; Jing      Wang; Yanhua      Cheng; Ronald      Gust

doi:10.2174/157340612801216418

Abstract

In order to develop a new series of dual inhibitors of SRC and ABL, and to investigate whether the pyrimidin- 4-ylamino moiety is critical for dasatinib’s activity, acetyl substitution was adopted as alternate scaffold at the 2-amino group. Eighteen novel dasatinib derivatives were developed by a parallel synthesis approach and evaluated for their antiproliferative effects. Preliminary tests showed that some of the target compounds IId, IIe and IIf manifested strong antiproliferative activity against MCF-7, MDA-MB 231 and HT-29 cells. Easpecially IId proved to be the most potent compound. Structure-activity relationship studies indicate that the introduction of acetyl substitution as alternate scaffold of pyrimidin-4-ylamino reduced the activity.

Keywords: Dasatinib, Antiproliferative Activity, SRC Kinase Inhibitor, Synthesis, Structure-Activity Relationship Studies, pyrimidin-4-ylamino, MDA-MB 231, HT-29 cells, ABL kinase, chronic myeloid leukaemia