Multi-Component Reactions of Cyclohexan-1,3-dione: Synthesis of Fused Pyran, Pyridine, Thiophene and Pyrazole Derivatives with c-Met, AntiProliferative Activities

(E-pub Abstract Ahead of Print)

Author(s): Rafat M. Mohareb*, Amira M. Elmetwally, Abeer A. Mohamed

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

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Background: Recently products of multi-component reactions (MCR’s) acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the pyran and pyridine nucleus that were produced through MCR’s were known.

Objective: We are aiming in this work to synthesize target molecules not only possess anti-tumour activities but also cMet and prostate cancer inhibitors. The target molecules were obtained starting from cyclohexan-1,3-dione through its multi-component reactions to produce anticancer target molecules.

Methods: Cyclohexan-1,3-dione underwent different multi-component reactions to produce fused pyran, pyridine and thiophene derivatives. The anti-proliferative activity of the newly synthesized compounds among the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. In addition, inhibitions toward c-Met kinase and prostate cancer cell line were studied. Antitumor evaluations toward seventeen cancer cell lines subpanel according the diseases, for certain compounds were also demonstrated. Pim-1 kinase inhibitions of the most active compounds were also measured.

Results: Anti-proliferative evaluations, c-Met and Pim-1 kinase inhibitions were performed for most of the synthesized compounds where the varieties of substituent through the aryl ring and the heterocyclic ring afforded compounds with high activities.

Conclusion: Compounds 4b, 6b, 8b, 9a, 11b, 12b, 17b, 18b, 19, 22c, 23b and 25b were the most cytotoxic compounds toward the six cancer cell lines. Inhibitions toward c-Met kinase and prostate cancer cell showed that the presence of the electronegative Cl group within the molecule was responsible for its high activity. In addition, inhibitions toward Pim-1 kinase exhibited that most of tested compounds showed high inhibitions.

Keywords: Cyclohexan-1, 3-dione, multi-component reactions, pyran, pyridine, thiophene, anti-proliferative

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(E-pub Abstract Ahead of Print)
DOI: 10.2174/1871520621666210112115128
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