Abstract
Combretastatin A-4 is a highly potent natural stilbene that can inhibit cancer cell proliferation. Numerous analogues of combretastatin A-4 have been proposed for clinical applications. However, structural studies of combretastatin A-2, a methylenedioxy derivative of combretastain A-4, are not available. In this study, various analogues of combretastatin A-2 with polymethylenedioxy spacer were prepared and their antiproliferative activities to four human cancer cell lines (HeLa, SK-OV-3, A549, and HT-29) and two normal cells (HaCaT and MDCK) were evaluated. Binding characteristics were evaluated based on computational docking and previously reported experimental data. Results suggest that their binding conformations are highly dependent on steric volume and electrostatic properties of substituents.
Highlights
Tubulin association is an important biological process targeted by many anti-proliferative agents
Molecular dynamic simulation has shown that the superior activity of combretastatin A-4 (CA-4) over its trans-isomer may result from stronger interaction between CA-4 and β-tubulin
Among the four cancer cell lines, HT-29, human colon colorectal adenocarcinoma cells were strongly inhibited by most synthetic stilbenes (IC50s = 0.009–1.9 μM), while the stilbenes showed a moderate antiproliferative activity on HeLa cells
Summary
Tubulin association is an important biological process targeted by many anti-proliferative agents. Molecular dynamic simulation has shown that the superior activity of CA-4 over its trans-isomer may result from stronger interaction between CA-4 and β-tubulin. SAR studies with bulkier analogues (e.g., 3,4,5-triethoxy in ring A) have shown lower activity which is indicative of small binding space around ring A [6]. Several polymethylenedioxy analogues of CA-2 were prepared and their cytotoxicities to several human cancer cell lines and normal cells were evaluated.
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