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

Author(s): Shirin Mollazadeh, Fatemeh Moosavi, Farzin Hadizadeh*, Mahmoud Seifi, Javad Behravan, Maryam Iman*.

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Volume 13 , Issue 2 , 2018

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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.

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Article Details

VOLUME: 13
ISSUE: 2
Year: 2018
Page: [255 - 264]
Pages: 10
DOI: 10.2174/1574892813666180220112613
Price: $58

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