A 2-step synthesis of Combretastatin A-4 and derivatives as potent tubulin assembly inhibitors

Abstract

A series of combretastatin derivatives were designed and synthesised by a two-step stereoselective synthesis by use of Wittig olefination followed by Suzuki cross-coupling. Interestingly, all new compounds (2a-2i) showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, 2a, 2b and 2e were the most active across three cancer cell lines. In addition, these compounds inhibited the polymerisation of tubulin in vitro more efficiently than CA-4. They caused cell cycle arrest in G2/M phase further confirming their ability to inhibit tubulin polymerisation.

Traditional Uses and Anticancer Potential of the Combretum Genus: A Literature Review

“…They consist of several series belonging to the stilbenoid class of compounds [62]. Several studies have been undertaken to highlight the anticancer properties of these compounds [63][64][65]. Combretastatins belonging to the A and B series present potent anticancer activity with the combretastatin A4 molecule being the most potent due to its broadspectrum cytotoxicity against a variety of tumor cells [66].…”

Novel chalcone-derived pyrazoles as potential therapeutic agents for the treatment of non-small cell lung cancer

“…Structurally, methoxylated chalcones are related to natural combretastatin A-4 and colchicine because of congruous spatial orientation between two aromatic rings 17 . Similar to combretastatin and colchicine, methoxylated chalcones bind to tubulin and prevent its polymerization, leading to cell cycle arrest by interruption of mitotic spindle assembly and resulting in cell death 18 .…”

Syntheses of Combretastatin A‐4 and Related Stilbenes by Using Aqueous Conditions

“…This selective Suzuki coupling has recently been improved to yield Z-CA4 (1 a) in an overall yield of 56 %. [13] In this method, the Z-vinyl iodide ( 14) was readily prepared using Stork-Zhao olefination methodology [14] from phosphonium iodide (13) and 3,4,5-trimethoxybenzaldehyde (12) in the presence of Sodium bis(trimethylsilyl)amide (NaHMDS, scheme 3). Suzuki-coupling of this Z-iodostyrene (14) compound with 3-hydroxy-4-methoxyphenyl boronic acid (15) produced solely Z-CA-4 (1 a) in 78 % yield, avoiding the need for protection and deprotection steps, and more importantly avoiding the use of highly toxic carbon tetrabromide and tin.…”

“…This selective Suzuki coupling has recently been improved to yield Z ‐CA4 ( 1 a ) in an overall yield of 56 % [13] . In this method, the Z ‐vinyl iodide ( 14 ) was readily prepared using Stork‐Zhao olefination methodology [14] from phosphonium iodide ( 13 ) and 3,4,5‐trimethoxybenzaldehyde ( 12 ) in the presence of Sodium bis(trimethylsilyl)amide (NaHMDS, scheme 3).…”

“… Improved Suzuki cross coupling synthesis of Z ‐CA‐4 [13] . Reagents and conditions : a) NaHMDS, THF, −20 to −78 °C, 2 h, 72 % ( 14 ); b) tetrakis (triphenylphosphine)palladium(0), sodium carbonate (Na 2 CO 3, 2 M), DME, 80 °C, 20 h, 78 % ( 1 a ).…”