New Approaches for the Synthesis of Fused Thiophene, Pyrazole, Pyran and Pyridine Derivatives with Anti-Proliferative Together with c-Met Kinase and Prostate Cancer Cell Inhibitions

Abstract

Background: Recently multi-component reactions producing pyran and pyridine derivatives acquired a special attention due to their wide range of pharmacological activities, especially therapeutic activities. Through the market, it was found that many pharmacological drugs containing the pyran and pyridine nucleus were known. Objective: We are aiming in this work to synthesize target molecules possess not only anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from cyclohexane-1,3-dione followed by its heterocyclization reactions to produce anticancer target molecules. Methods: This work demonstrated multi-component reactions of cyclohexan-1,3-dione with aromatic aldehydes and diethylmalonate using triethylamine as a catalyst to give the 7,8-dihydro-4H-chromen-5(6H)-one derivatives 4a-c. The reaction of compounds 4a-c with either of hydrazine hydrate of phenylhydrazine gave the chromeno[2,3-c]pyrazole derivatives 5a-f, respectively. In addition, further heterocyclization reactions were adopted to give the chromeno[3,2-d]isoxazole, chromene-3-carboxamide derivatives. Moreover, the multicomponent reaction of cyclohexan-1,3-dione (1) with either of aromatic aldehydes and diethylmalonate using a catalytic amount of ammonium acetate gave the 1,4,5,6,7,8-hexahydroquinoline derivatives 13a-c. The antiproliferative activities of the synthesized compounds toward the six cancer cell lines namely A549, H460, HT- 29, MKN-45, U87MG, and SMMC-7721 were studied. In addition, the c-Met enzymatic activities and inhibition toward the prostate cancer cell PC-3 were measured. Results: Anti-proliferative evaluations, c-Met enzymatic activities and inhibition toward the prostate cancer cell PC-3 were measured, and the results obtained in most cases indicated that the presence of electronegative Cl group through the molecule favour the inhibitions. Conclusion: The compounds with high anti-proliferative activity towards the cancer cell lines were 4a, 4b, 6d, 6e, 6f, 10e, 10f, 12c, 14e, 14f, 15c, 16d, 16e, 16f, 19c and 20c. Compounds 4b, 6c, 6d, 8b, 10c, 10d, 12b, 13b, 14c, 14d, 15b, 16c, 16d, 17b, 17c, 19b, 20b and 20c exhibited high potency against c-Met kinase and compounds 4a, 4b, 6b, 6c, 6d, 6f, 8b, 8c, 10c, 10d, 10e, 12b, 12c, 13a, 13b, 13c, 14c, 14d, 14e, 14f, 15b, 15c, 16b, 16c, 16d, 17b, 17c, 19c, 19d, 20a, 20b and 20c displayed high inhibitions toward PC-3 cell line.