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

Author(s):

Rafat M. Mohareb*, Amira M. Elmetwally and Abeer A. Mohamed   Pages 2443 - 2463 ( 21 )

Abstract:

<P>Background: Recently, products of Multi-Component Reactions (MCR’s) acquired special attention due to their wide range of pharmacological activities especially therapeutic activities. In the market it was found that many pharmacological drugs containing the pyran and pyridine nucleus that were produced through MCR’s were found. </P><P> Objective: This work aims to synthesize target molecules not only possess anti-tumour activities but also c-Met 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. </P><P> Methods: Cyclohexane-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, for certain compounds, were also demonstrated according to the diseases. Pim-1 kinase inhibitions of the most active compounds were also measured. </P><P> 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. </P><P> Conclusion: Compounds 4b, 6b, 8b, 9a, 11b, 12b, 17b, 18b, 19, 22c, 23b, 25b and 26b were the most cytotoxic compounds toward the six cancer cell lines. Inhibitions toward c-Met kinase and prostate cancer cells showed that the presence of the electronegative Cl group within the molecule were responsible for its high activity. In addition, inhibitions toward Pim-1 kinase exhibited that most of tested compounds showed high inhibitions.</P>

Keywords:

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

Affiliation:

Department of Chemistry, Faculty of Science, Cairo University, Giza, National Organization for Drug Control and Research (NODCAR) P.O. 29, Cairo, National Organization for Research and Control of Biologicals.51 Wezaret El-Zeraa St, Dokki, Giza

Graphical Abstract:

Read Full-Text article