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

Abstract

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.