869497-71-2Relevant articles and documents
Synthesis and evaluation of antiproliferative microtubule-destabilising combretastatin A-4 piperazine conjugates
O'Boyle, Niamh M.,Ana, Gloria,Kelly, Patrick M.,Nathwani, Seema M.,Noorani, Sara,Fayne, Darren,Bright, Sandra A.,Twamley, Brendan,Zisterer, Daniela M.,Meegan, Mary J.
supporting information, p. 6184 - 6200 (2019/07/04)
Microtubules are a validated clinical target for the treatment of many cancers. We describe the design, synthesis, biochemical evaluation, and molecular modelling studies of a series of analogues of the microtubule-destabilising agent, combretastatin A-4 (CA-4). Our series of 33 novel compounds contain the CA-4 core structure with modifications to the stilbene linking group, and are predominantly piperazine derivatives. Synthesis was achieved in a two-step process by firstly obtaining the acrylic acid via a Perkin reaction using microwave enhanced synthesis, followed by coupling using either DCC or Mukaiyama's reagent. All target compounds were screened for antiproliferative activity in MCF-7 breast cancer cells. Hydroxyl derivative (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-2-(3,4,5-trimethoxyphenyl) propenone (4m) displayed potent antiproliferative activity (IC50 = 190 nM). Two amino-containing derivatives, (E)-3-(3-amino-4-methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4q) and (E)-3-(3-amino-4-methoxyphenyl)-1-(4-(p-tolyl)piperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4x), were the most potent with IC50 values of 130 nM and 83 nM respectively. Representative compounds were shown to depolymerise tubulin, induce G2/M arrest and apoptosis in MCF-7 cells but not peripheral blood mononuclear cells, and induce cleavage of the DNA repair enzyme poly ADP ribose polymerase (PARP) in MCF-7 cells. Modelling studies predict that the compounds bind to tubulin within the colchicine-binding site. These compounds are a valuable addition to the library of CA-4 analogues and 4m, 4q and 4x will be developed further as novel, water-soluble molecules targeting microtubules.
Practical and green synthesis of combretastatin A-4 and its prodrug CA4P using renewable biomass-based starting materials
Chen, Yu,Zou, Yong,Sun, Hong-Yi,Liu, Xian-Ke,Xiao, Chun-Fen,Sun, Jie,He, Shu-Jie,Li, Jun
experimental part, p. 217 - 222 (2011/02/28)
A practical and green protocol for the synthesis of vascular disrupting agent combretastatin A-4 (CA4) and its water soluble prodrug CA4P is described. Starting from the biomass-based compound anethole, which is abundantly and sustainably available from Chinese star anise (Illicium verum Hook. f.), the key intermediate 3-hydroxy-4-methoxyphenylacetic acid can be obtained within five steps. Perkin condensation between this acid and another naturally derived compound 3,4,5-trimethoxybenzaldehyde, followed by decarboxylation gives combretastatin A-4 in good overall yield. The phosphate produrg CA4P can be prepared under simple and mild conditions in a sequential one-pot two-step reaction. Georg Thieme Verlag Stuttgart New York.
Synthesis of combretastatin A-4 and erianin
Zou, Yong,Xiao, Chun-Fen,Zhong, Rong-Qing,Wei, Wen,Huang, Wen-Ming,He, Shu-Jie
experimental part, p. 354 - 356 (2009/06/18)
A concise route to two anti-tubulin natural products combretastatin A-4 and erianin has been developed. Combretastatin A-4 was obtained by a Perkin reaction between 3-bromo-4-methoxyphenyl acetic acid and 3,4,5- trimethoxybenzaldehyde, hydroxyl transformation, decarboxylation with a high level of cis-selectivity (cis/trans = 95/5), and erianin was obtained by subsequent hydrogenation. The overall yields of combretastatin A-4 and erianin were 37.5 and 30.8%, respectively.
