Evaluation Of 5-hydroxy-2,3-diaryl (substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anti angiogenic and anticancer agents

Abstract

Two potent cis-restricted CA-4 analogues 11 and 42 belonging to 2,3-diaryl-5-hydroxycyclopent-2-en-1-one class were evaluated for anticancer and anti angiogenic activity. The compound 42 displayed potent cytotoxic activity (IC(50) < 1 muM) against a panel of human cancer cell lines viz PTC, MDA.MB.453, PA1, SKOV3, DU145 and Miapaca2, whereas compound 11 displayed cytotoxicity activity (IC(50) < 1 microM) only in Miapaca2. Both the compounds inhibit growth factor stimulated endothelial cell proliferation, migration and capillary tube formation. In all the above parameter compound 42 was superior to 11. Based on the above results compound 42 was assessed for inhibition of vasculature in vivo and showed significant inhibition at 25 mg/kg dose. Further it was evaluated for in vivo anti tumor activity in athymic mice bearing DU145 and SKVO3 tumor xenograft and showed regression in tumor volume (T/C) of 23.8% (CA-4), 50.1% (compound 42) and 23.5% (CA-4), 56% (compound 42) respectively at a dose of 20 mg/kg (i.v.) daily for 14 days.

Combretastatins: More Than Just Vascular Targeting Agents?

“…Furthermore, in this study, CA-4P inhibited sprout formation at concentrations that did not inhibit the proliferation of endothelial cells, confirming direct antiangiogenic properties of CA-4P. Similarly, modulation of endothelial cells by combretastatin analogs has been reported in vitro (Dupeyre et al, 2006;Kong et al, 2010;Romagnoli et al, 2010;Sanna et al, 2010;Arthuis et al, 2011;Porcù et al, 2013) and in vivo (Fortin et al, 2011;Porcù et al, 2013;Zheng et al, 2014). The molecular mechanism of the antiangiogenic properties of TR-644 CA-4 analog was linked to the inhibition of vascular endothelial growth factor-induced phosphorylation of VE-cadherin (Porcù et al, 2013).…”

Agarose multi-wells for tumour spheroid formation and anti-cancer drug test

“…To study the anticancer drug effect, CA4 was added in the medium after culture for 3 days, which is a stilbene inhibits tubulin polymerization at the colchicine-binding site of tubulin and high cytotoxic against a variety of human cancer cells including some multidrug resistant cancer cell lines [17,18]. As expected, the spheroid stopped to grow and some of the cells were detached from the spheroid (Fig.4).…”