Novel Combretastatin Analogues Endowed with Antitumor Activity

Abstract

We studied the anticancer activity of a series of new combretastatin derivatives with B-ring modifications. The structure-activity relationship (SAR) information confirmed the importance of cis-stereochemistry and of a phenolic moiety in B-ring. We selected the benzo[b]thiophene and benzofuran combretastatin analogues 11 (ST2151) and 13 (ST2179) and their phosphate prodrugs (29 and 30) for their high antitumor activity in in vitro and in vivo models. Cell exposure to IC50 of 11, 13, and CA-4 led to the arrest of various cell types in the G2/M phase of the cell cycle and induction of apoptosis. Mainly, 11 and 13 induced the formation of multinucleated cells with abnormal chromatin distribution, with only a minimal effect on the microtubule organization, with respect to CA-4. Interestingly, both the pharmacokinetic profile of 29 and its in vivo antitumor effect and those of 30, active even after oral administration, suggest additional pharmacological differences between these compounds and CA-4P.

Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe

“…Mitotic catastrophe has also been demonstrated for 4 and related derivatives in both human endothelial cells (HUVEC) and human lung carcinoma cells (H460) [35]. Taken together, these results confirm tubulin as the molecular target of this series of β-lactam combretastatin derivatives and demonstrate mitotic catastrophe in MCF-7 breast cancer cells for 4 and 26 for the first time.…”

Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents

“…Additionally, cells treated with 2 or β-lactam 90b contained multiple micronuclei, a phenomenon described as mitotic catastrophe. 37 The findings are in agreement with previous reports that 2 induced mitotic catastrophe in non-small cell lung cancer cells, [38][39] human endothelial cells (HUVEC), 40 human lung carcinoma cells (H460) 40 and human breast cancer cells (MCF-7). 41 Taken in conjuction with the effects on polymerization of isolated tubulin, the confocal imaging results confirm that β-lactam 90b is targeting tubulin.…”

Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity

“…A variety of small molecules with diverse molecular scaffolds have been shown to bind tubulin at the colchicine site [6][7][8][9]. One class of these compounds receiving particular attention has been that based on the natural product combretastatin A-4 discovered by Pettit [10,11]. Despite some successes, the discovery of new, more efficacious inhibitors is becoming increasingly important because of multi-drug resistance to tubulin-binding antimitotic agents [12].…”