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

[ Vol. 13 , Issue. 2 ]

Author(s):

Shirin Mollazadeh, Fatemeh Moosavi, Farzin Hadizadeh*, Mahmoud Seifi, Javad Behravan and Maryam Iman*   Pages 255 - 264 ( 10 )

Abstract:


Background: 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.

Objective: In this study, new compounds of 1,4-dihydropyridine (DHP) were recommended as inhibitors of P-gp.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords:

DFT study, 1, 4-dihydropyridine, Hantzsch reaction, molecular orbital, P-glycoprotein, synthesis.

Affiliation:

Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Department of Chemistry, Ferdowsi University of Mashhad, Mashhad 9177948974, Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Chemical Injuries Research Center, System Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran



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