Synthesis of tetrahydropyrazolo-quinazoline and tetrahydropyrazolo-pyrimidocarbazole derivatives as potential anti-prostate cancer agents and Pim-1 kinase inhibitors

Abstract

The multi-component reactions of arylhydrazopyrazoles 2, aromatic aldehydes 3 and cylohexane-1,3-dione gave pyrazoloquinazolinones 5. In addition, compounds 5 reacted with elemental sulfur and either of malononitrile or ethyl cyanoacetate to give the thiophene derivatives 7, respectively. Compounds 5 were used to synthesis the 5,6,11,12-tetrahydro-3H-pyrazolo[1’,5’:1,2]pyrimido[5,4-a]carbazol-2-ol derivatives 9 through their reaction with phenylhydrazine. Similarly, the reaction of the pyrazole derivatives 2, with 3 and dimedone (10) gave the quinoline derivatives 11. The newly synthesized products were evaluated against c-Met kinase, PC-3 prostate cancer cell lines and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). The most promising compounds were 5b, 5c, 5e–i, 7e, 7p, 7q, 7r, and 11i were further investigated against tyrosin kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Some compounds were selected to examine their Pim-1 kinase inhibition activity where compounds 5h and 7u showed high inhibitions.