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 μM), 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.