Discovery of a New Chalcone-Trimethoxycinnamide Hybrid with Antimitotic Effect: Design, Synthesis, and Structure-Activity Relationship Studies

In this work, the design and synthesis of a new chalcone-trimethoxycinnamide hybrid (7) based on the combination of subunits of two promising antiproliferative compounds (CM-M345 (1) and BP-M345 (2)), previously obtained by our research group, are reported. In order to expand the structure-activity relationship (SAR) knowledge, a new series of 7-analogues was also designed and synthetized. All the compounds were evaluated for their antitumor activity against melanoma (A375-C5), breast adenocarcinoma (MCF-7), and colorectal carcinoma (HCT116) cell lines, as well as non-tumor HPAEpiC cells. Three of the newly synthesized compounds (6, 7, and 13) exhibited potent antiproliferative activity, mainly on colorectal tumor cells (GI(50) = 2.66-3.26 & mu;M), showing hybrid 7 selectivity for tumor cells. We performed molecular mechanism studies to evaluate the potential interference of compounds with the p53 pathway, namely, p53-MDM2 interaction and mitosis in HCT116 cells. The antiproliferative activities of compounds were shown to be p53-independent. Compound 7 emerged as an antimitotic agent by inducing the mitotic arrest of colorectal tumor cells, and subsequently, cell death.

Automated summary

This article reports the design and synthesis of a new chalcone-trimethoxycinnamide hybrid (7) based on two promising antiproliferative compounds (CM-M345 and BP-M345). A new series of 7-analogues was also designed and synthesized to expand the structure-activity relationship (SAR) knowledge. The antitumor activity of these compounds was evaluated against melanoma, breast adenocarcinoma, colorectal carcinoma, and non-tumor cells. Compound 7 showed potent antiproliferative activity on colorectal tumor cells, and its mechanism of action was found to be p53-independent and involved inducing mitotic arrest and cell death.