Novel A-Ring and B-Ring Modified Combretastatin A-4 (CA-4) Analogues Endowed with Interesting Cytotoxic Activity

Abstract

A novel class of combretastatins, modified at A-ring or both A- and B-rings, mainly by replacement with benzofuran or benzo[b]thiophene, were synthesized. The new heterocombretastatins showed good cytotoxic activity on BMEC and H-460 cell lines. The aminocombretastatin 9f potently inhibits cell growth of BMEC and combretastatin-resistant HT-29 cell lines, with potential interest to treat colon carcinoma. Heterocombretastatins 9a,b inhibit tubulin polymerization similarly to CA-4 by having a binding to colchicine site five times stronger.

Synthesis, biological evaluation and molecular docking studies of trans-indole-3-acrylamide derivatives, a new class of tubulin polymerization inhibitors

“…5 CA-4 has provided researchers a simple structural template for the design of related compounds with potent activity and a large number of combretastatin analogues have been prepared as potential anticancer agents including chalcones, some of which have recently been reviewed. 6–10 Chalcones (1,3-diaryl-2-propen-1-ones) with an ionone system between two aromatic rings (Fig. 1) serve as precursors for the preparation of various flavonoids and exhibit interesting pharmacological activities 11, 12 such as anticancer 13– 15 and antiproliferative activities.…”

Synthesis and Cytotoxic Activity of a New Group of Heterocyclic Analogues of the Combretastatins

“…A water soluble disodium phosphate derivative of CA-4 (CA-4P, fosbretabulin) has shown promising results in human cancer clinical trials [3,4], thus stimulating significant interest in a variety of CA-4 analogues [5]. Different analogs of combretastatins are obtained, including heterocombretastatins containing heterocyclic fragments as rings A or B [6][7][8][9][10][11][12]. A considerable cytotoxicity and antitubulin activity was revealed for heterocombretastatins containing a (4-methoxypyridin-3-yl)-or a (1-methyl-2-oxo-1,2-dihydropyridin-4-yl) ring B [6].…”

“…A considerable cytotoxicity and antitubulin activity was revealed for heterocombretastatins containing a (4-methoxypyridin-3-yl)-or a (1-methyl-2-oxo-1,2-dihydropyridin-4-yl) ring B [6]. Compounds with benzo [b]furan ring B [9,10] or A [10], attached to the 6 position, demonstrated high antitumor activity in in vitro and in vivo models. In more recent works, replacement of the B-ring of CA-4 (1) with a (benzofuran-2-yl) moiety was also examined and the activity of the benzofuranyl derivatives was evaluated [11,12].…”

Enhanced antitumor activity by the combination of dasatinib and combretastatin A-4 in vitro and in vivo

“…CA-4 phosphate (CA-4P), a water soluble pro-drug of CA-4, is rapidly dephosphorylated to the active compound CA-4 and shows reversible binding kinetics to tubulin, leading to disruption of microtubular structures (2,3). Although CA-4P is being studied in clinical trials as a vascular disrupting agent, cardiovascular toxicity and neurotoxicity are dose limiting for CA-4P (4,5).…”

“…Although CA-4P is being studied in clinical trials as a vascular disrupting agent, cardiovascular toxicity and neurotoxicity are dose limiting for CA-4P (4,5). These severe side-effects currently represent the main obstacles to broad clinical application of CA-4P (2). Thus, it is important to develop new antitumor combination therapy with lower concentrations of CA-4 and more specificity for tumor endothelial cells than normal endothelial cells to avoid cardiac toxicity from endothelial damage.…”