Design, Synthesis and Biological Evaluation of Novel Analogs of Bortezomib

Abstract

Novel analogs of bortezomib were designed, synthesized and in vitro biological evaluation was carried out using human tumor cell lines A549 and PC3. Docking studies of these analogs of bortezomib was discussed. According to biological investigations, the inhibitors 4, 6, and 8 were found to be more potent than reference drug candidate bortezomib. A549 cell line showed significant sensitivity towards 4, 6, and 8 with IC 50 values 14.03, 18.5, and 12.4 nM, respectively, and PC3 cell line showed IC 50 values 26.1, 37.0, and 21.2 nM, respectively. The IC 50 values of bortezomib in these cell lines are 27.3 nM and 42.0 nM.

Peptide‐Based Proteasome Inhibitors in Anticancer Drug Design

“…Considering the P 3 position, SAR analysis indicated that only substituents such as 2‐pyrazyl or tetrahydronaphthalen‐1‐yl are beneficial to the potency; small alkyl groups (e.g., CH 3 ) or more hindered groups (e.g., tert ‐butoxy) led to loss of potency. This position has been recently further explored in bortezomib‐like compounds by an Indian research group that obtained derivatives with significant cytotoxicity (nanomolar range) toward human tumor cells A549 and PC‐3 …”