Abstract
We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3’’-amino-4’’-methoxyphenyl)-1-(5’-methoxy-3’,4’-methylendioxyphenyl)-2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-to-straight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs.
Highlights
Cancer is a leading cause of death worldwide and its occurrence is expected to double in the following decades [1]
X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and prevent the curved-tostraight structural transition of tubulin, which is required for microtubule formation
The synthesis of the chalcones involved an aldol condensation between a phenone fused to a dioxolane ring (A ring) and the corresponding benzaldehyde
Summary
Cancer is a leading cause of death worldwide and its occurrence is expected to double in the following decades [1]. The selectivity of VDAs for tumor endothelium versus physiological vessels lies in the crucial differences between these vessels [4, 6]. Tumor vessels are characterized by a higher www.impactjournals.com/oncotarget proliferation rate and the lack of pericytes and a proper basement membrane, which makes them more fragile and tortuous than physiological vessels [6, 7]. Overall, this results in increased vascular permeability and a higher resistance to blood flow, making the tumor vasculature more sensitive to any variation in perfusion pressure [8, 9]
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