Abstract
3,4-Dihydropyrimidin-2(1H)-one/thione analogs of curcumin were synthesized in good yield by a one-pot multi-component cyclocondensation using curcumin, substituted aromatic aldehydes, and urea/thiourea in ethanol and concentrated sulphuric acid. The National Cancer Institute (NCI US) Protocol was followed, and three compounds were evaluated for their anticancer evaluation on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers cell lines. 6-(4-Hydroxy-3-methoxy)-4-(4-methoxyphenyl)-3,4-dihydro-5-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]pyrimidin-2(1H)-one (2) showed maximum activity with mean growth percent of 88.90 and found to be the most sensitive on MDA-MB-231/ATCC (Breast Cancer), PC-3 (Prostate Cancer), SNB-75 (CNS Cancer), RPMI-8226 (Leukemia), MOLT-4 (Leukemia), CCRF-CEM (Leukemia), and HS 578T (Breast Cancer) cell lines with GP of 58.50, 59.60, 60.07, 64.11, 72.84, and 73.39, respectively. The molecular docking studies were also performed to explore the binding mode of the compounds to EGFR tyrosine kinase active site. Compound 4 showed the side-chain hydrogen bond with the residues Asp800 and Thr854, and we also observed the π–cation interactions with methyl group of Lys745. The 4-chlorophenyl part was influenced by the aromatic interactions. The compounds 2 and 7 showed the similar interactions with residues Arg841. Compound 4 showed the hydrogen bonding with residues Met793, Lys745, and Met766, whereas compound 2 showed hydrogen bonding with Met893, Asp800, and Thr854, and compound 7 showed a different hydrogen bonding with the residues Met793, Lys745, Asp800, and Asp855. The aromatic π–π cationic interactions were observed with residue Phe723 in common with the compounds 2, 4, and 7.
Graphical Abstract
3,4-Dihydropyrimidin-2(1H)-one/thione analogs of curcumin were synthesized in good yield by a one-pot multi-component cyclocondensation using curcumin, substituted aromatic aldehydes, and urea/thiourea in ethanol and concentrated sulphuric acid. Among the series of 15, 3,4-dihydropyrimidin-2(H)-one/thione analogs of curcumin, 6-(4-Hydroxy-3-methoxy)-4-(4-methoxyphenyl)-3,4-dihydro-5-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]pyrimidin-2(1H)-one (2) showed maximum anticancer activity on various cancer cell lines, with mean growth percent (GP) of 88.90. The molecular docking studies were also performed to explore the binding mode of the compounds to EGFR tyrosine kinase active site. Binding mode of compound 2 with EGFR tyrosine kinase active site
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Acknowledgments
The anticancer data were provided by the National Cancer Institute (NC US), Bethesda, MD, USA. We are also grateful for all help provided by Prof. Doug Smallwood and Mr. Mohammed Nayel. The management of Maharishi Arvind College of Pharmacy, Jaipur, Rajasthan, India is acknowledged for providing research facilities.
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Sharma, R., Jadav, S.S., Yasmin, S. et al. Simple, efficient, and improved synthesis of Biginelli-type compounds of curcumin as anticancer agents. Med Chem Res 24, 636–644 (2015). https://doi.org/10.1007/s00044-014-1146-2
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DOI: https://doi.org/10.1007/s00044-014-1146-2