A New Naphthopyran Derivative Combines c -Myb Inhibition, Microtubule-Targeting Effects, and Antiangiogenic Properties.

Based on the promising c -Myb inhibitor 1b , a series of 2-amino-4-aryl-4 H -naphtho[1,2- b ]pyran-3-carbonitriles ( 1a , 2a - q , 3a - g ) were repurposed or newly synthesized via a three-component reaction of 1-naphthol, and various aryl aldehydes and malononitrile and screened for their c -Myb inhibitory activities. 1b also served as a lead compound for seven new naphthopyran derivatives ( 3a - f ), which were cytotoxic with nanomolar IC 50 values, to inhibit the polymerization of tubulin, and to destabilize microtubules in living cells. Especially, the alkyne 3f , originally made for intracellular localization studies using click chemistry, showed an overall high activity in all assays performed. A strong G2/M cell cycle arrest was detected, which resulted in a distinct increase in sub-G1 cells through the induction of effector caspases 3 and 7. Inhibition of angiogenesis was confirmed in vitro and in vivo . In summary, 3f was found to be a pleiotropic compound with high selectivity for cancer cells, combining c- Myb inhibitory, microtubule destabilizing, and antiangiogenic effects.