Synthesis and DFT study on Hantzsch reaction to produce asymmetrical compounds of 1,4-dihydropyridine derivatives for P-glycoprotein inhibition as anticancer agent

Abstract

BACKGROUND:<br><br>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.<br><br><br><br>OBJECTIVE:<br><br>In this study, new compounds of 1,4-dihydropyridine (DHP) were recommended as inhibitors of P-gp.<br><br><br><br>METHODS:<br><br>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.<br><br><br><br>RESULTS:<br><br>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.<br><br><br><br>CONCLUSION:<br><br>In this study, selected reactants by DFT calculation have increased the yield of reaction from 36% to 74% without any catalyst. The diversity of products is a noticeable topic. Racemic asymmetric compounds with R and S enantiomers have the potential for enantiomeric separation. Each of these enantiomers could have a different physiological effect.