Uses of dimedone for the synthesis of new heterocyclic derivatives with anti-tumor, c-Met, tyrosine, and Pim-1 kinases inhibitions

The reaction of dimedone ( 1 ) with any of the diazonium salts 2a–c to give the arylhydrazone derivatives 3a–c . The Gewald’s reaction of any of compounds 3a–c using elemental sulfur and either of malononitrile or ethyl cyanoacetate gave the thiophene derivatives 5a–f , respectively. Compounds 5a , 5c , and 5e underwent a series of heterocclization reactions to give potentially anticancer agents. The newly synthesized compounds were evaluated for their in vitro cytotoxic activity against c-Met kinase, and the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). All target compounds were initially tested for their anti-proliferative activity against human prostatic cancer PC-3 cell line. The most promising compounds were 5c , 6c , 6d , 8e , 8f , 12d , 14e , and 14f were further investigated against tyrosin kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 3c, 5c, 5d, 6c, 6d, 8f, 8g, 8h, 12c, 12d , 12f , and 14f were selected to examine their Pim-1 kinase inhibition activity where compounds 3c , 6c , 8g , 12c , and 14f showed high activities.