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D. Chen, Y. Hu, R. Mott, P.-K. Li, J.-X. Ma; Anti-Angiogenic Activities of Novel Combretastatin A4 Analogs. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4589.
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Abnormal angiogenesis in the retina or retinal neovascularization (NV) is one of the major pathological changes in diabetic retinopathy (DR). Retinal NV can ultimately result in severe vitreous cavity hemorrhage and/or retinal detachment, leading to severe loss of vision. There is no satisfactory pharmacotherapy for DR. Cis combretastatin A4 (CA4) is a tubulin-binding agent originally isolated from the South African shrub Combretum caffrum. Previous studies have demonstrated that CA4 and combretastatin A4 phosphate (CA4P) have inhibitory activities on tubulin polymerization, rapidly proliferating tumor vasculature and retinal NV. To develop more potent and less toxic anti-angiogenic drugs, we have synthesized a series of novel CA4 analogs and evaluated their activities.
Using SU5416 (an inhibitor of VEGF receptor tyrosine kinase) as a template, a series of CA4 analogs were designed and synthesized. MTT assay was used to determine the growth inhibitory activities of CA4 analogs in cancer cells, PC-3 and MDA-MB-231, bovine retinal capillary endothelial cells (BRCECs) and pericytes. The inhibitory effect of CA4 analogs on tubulin polymerization was assessed by tubulin assembly assay.
Among 25 new compounds, four compounds (Compounds 1 and 9, SU168, and SU178), which structurally resemble CA4 and SU5416, possess potent growth inhibitory activities in PC-3 and MDA-MB-231 cell lines with an IC50 of 0.9 -108.5 nM. Compound 1 and SU168 inhibited the proliferation of BRCECs in a dose-dependent manner with an IC50 of 14.8 and 84.2 nM, respectively. These compounds did not significantly inhibit the growth of pericytes (IC50 > 640 nM), suggesting specific inhibition to endothelial cells. These compounds also inhibited tubulin polymerization with an IC50 of 4.5-19.8 nM.
CA4 analogs Compound 1 and SU168 have potent anti-angiogenic activities.
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