Synthesis and DFT Study on Hantzsch Reaction to Produce Asymmetrical Compounds of 1,4-Dihydropyridine Derivatives for P-Glycoprotein Inhibition as Anticancer Agent

Recent Patents on Anti-cancer Drug Discovery
Shirin MollazadehMaryam Iman

Abstract

P-glycoprotein (P-gp) causes the efflux of cancer chemotherapy drugs from tumor cells, so its inhibition can be one target for designing and synthesis of new anticancer drugs. In this study, new compounds of 1,4-dihydropyridine (DHP) were recommended as inhibitors of P-gp. We synthesized new symmetrical DHP with 36% - 43% yield by the reaction of new reactants. In biological studies, these compounds have high lipophilicity, and thus low water solubility. Four reactants I with different reactivity was computed and compared using DFT study. The LUMO-map was differently distributed on each reactant. Amine intermediate underwent tautomerism as a transition state and it seems to play important role in reaction progress. Calculations were performed to select suitable reactants. Two different reactants I, including one polar group and a non-polar group, were used to produce asymmetric compounds with 49% - 60% yield. These asymmetric DHPs were more soluble than symmetric DHPs. In the final step, another selected symmetric product (by the elimination of chlorine atom) was synthesized in high yield (74%) by using DFT study. In this study, selected reactants by DFT calculation have increased the yield of reaction from 36% to 74% without a...Continue Reading

Citations

Jun 24, 2020·Journal of Biomolecular Structure & Dynamics·Shirin MollazadehRicardo J Ferreira
May 23, 2020·International Journal of Molecular Sciences·Ming-Han LeeMax K Leong

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