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Issue 25, 2019
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Synthesis and evaluation of antiproliferative microtubule-destabilising combretastatin A-4 piperazine conjugates

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Abstract

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.

Graphical abstract: Synthesis and evaluation of antiproliferative microtubule-destabilising combretastatin A-4 piperazine conjugates

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Supplementary files

Article information


Submitted
08 3 2019
Accepted
28 5 2019
First published
29 5 2019

Org. Biomol. Chem., 2019,17, 6184-6200
Article type
Paper

Synthesis and evaluation of antiproliferative microtubule-destabilising combretastatin A-4 piperazine conjugates

N. M. O'Boyle, G. Ana, P. M. Kelly, S. M. Nathwani, S. Noorani, D. Fayne, S. A. Bright, B. Twamley, D. M. Zisterer and M. J. Meegan, Org. Biomol. Chem., 2019, 17, 6184
DOI: 10.1039/C9OB00558G

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