Numerous members of the combretastatin and chalcone families of natural products function as inhibitors of tubulin polymerization through a binding interaction at the colchicine site on β-tubulin. These molecular scaffolds inspired the development of many structurally modified derivatives and analogues as promising anticancer agents. A productive design blueprint that involved molecular hybridization of the pharmacophore moieties of combretastatin A-4 (CA4) and the chalcones led to the discovery of two promising lead molecules referred to as KGP413 and SD400. The corresponding water-soluble phosphate prodrug salts of KGP413 and SD400 selectively damaged tumor-associated vasculature, thus highlighting the potential development of these molecules as vascular disrupting agents (VDAs). These previous studies prompted our current investigation of conformationally restricted chalcones. Herein, we report the synthesis of cyclic chalcones and related analogues that incorporate structural motifs of CA4, and evaluation of their cytotoxicity against human cancer cell lines [NCI-H460 (lung), DU-145 (prostate), and SK-OV-3 (ovarian)]. While these molecules proved inactive as inhibitors of tubulin polymerization (IC50 > 20 μM), eight molecules demonstrated good antiproliferative activity (GI50 < 20 μM) against all three cancer cell lines, and compounds 2j and 2l demonstrated sub-micromolar cytotoxicity. To the best of our knowledge these molecules represent the most potent (based on GI50) cyclic chalcones known to date, and are promising lead molecules for continued investigation.