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, originally made for intracellular localization studies using click chemistry, showed an overall high activity in all assays performed.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