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Antimitotic agents that interfere with microtubule formation are one of the major classes of cytotoxic drugs for cancer treatment. Multiple 2-methyl-4-(3′,4′,5′-trimethoxyphenyl)-5-substituted oxazoles and their related 4-substituted-5-(3′,4′,5′-trimethoxyphenyl) regioisomeric derivatives designed as  cis -constrained combretastatin A-4 (CA-4) analogues were synthesized and evaluated for their antiproliferative activity  in vitro  against a panel of cancer cell lines and, for selected highly active compounds, interaction with tubulin, cell cycle effects and  in vivo  potency. Both these series of compounds were characterized by the presence of a common 3′,4′,5′-trimethoxyphenyl ring at either the C-4 or C-5 position of the 2-methyloxazole ring. Compounds  4g  and  4i , bearing a  m -fluoro- p -methoxyphenyl or  p -ethoxyphenyl moiety at the 5-position of 2-methyloxazole nucleus, respectively, exhibited the greatest antiproliferative activity, with IC 50  values of 0.35-4.6 nM ( 4g ) and 0.5–20.2 nM ( 4i ), which are similar to those obtained with CA-4. These compounds bound to the colchicine site of tubulin and inhibited tubulin polymerization at submicromolar concentrations. Furthermore,  4i  strongly induced apoptosis that follows the mitochondrial pathway.  In vivo ,  4i  in a mouse syngeneic model demonstrated high antitumor activity which significantly reduced the tumor mass at doses ten times lower than that required for CA-4P, suggesting that  4i  warrants further evaluation as a potential anticancer drug.

Synthesis and Biological Evaluation of 2-Methyl-4,5-Disubstituted Oxazoles as a Novel Class of Highly Potent Antitubulin Agents