2‐Amino‐4‐aryl‐5‐oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐carbonitriles with Microtubule‐Disruptive, Centrosome‐Declustering, and Antiangiogenic Effects in vitro and in vivo

A series of fifteen 2‐amino‐4‐aryl‐5‐oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐carbonitriles (1 a–o) were synthesized via a three‐component reaction of 4‐hydroxycoumarin, malononitrile, and diversely substituted benzaldehydes or pyridine carbaldehydes. The compounds were tested for anticancer activities against a panel of eight human tumor cell lines. A few derivatives with high antiproliferative activities and different cancer cell specificity were identified and investigated for their modes of action. They led to microtubule disruption, centrosome de‐clustering and G2/M cell cycle arrest in 518 A2 melanoma cells. They also showed anti‐angiogenic effects in vitro and in vivo. De‐clustering cancer: A new 2‐amino‐4‐aryl‐5‐oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐carbonitrile with superior anticancer activity was identified. While selectively targeting cancer cells through centrosome de‐clustering, angiogenesis was significantly decreased in vitro and in vivo.