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Isoform selectivity of harmine-conjugated 1,2,3-triazoles against human monoamine oxidase.

ABSTRACT: AIM:There is little information available on the monoamine oxidase isoform selectivity of N-alkyl harmine analogs, which exhibit a myriad of activities including MAO-A, DYRK1A and cytotoxicity to several select cancer cell lines. RESULTS:Compounds 3e and 4c exhibited an IC50 of 0.83 ± 0.03 and 0.43 ± 0.002 ?M against MAO-A and an IC50 of 0.26 ± 0.04 and 0.36 ± 0.001 ?M against MAO-B, respectively. Molecular docking studies revealed ?-? interactions between the synthesized molecules and aromatic amino acid residues. Conclusion & future perspective: The current study delineates the structural requirements for MAO-A selectivity and such information may be helpful in designing selective analogs for kinase, DYRK1A and harmine-based cytotoxics without apparent MAO enzyme inhibition.

SUBMITTER: Haider S

PROVIDER: S-EPMC6021913 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Isoform selectivity of harmine-conjugated 1,2,3-triazoles against human monoamine oxidase.

Haider Saqlain S Alhusban Manal M Chaurasiya Narayan D ND Tekwani Babu L BL Chittiboyina Amar G AG Khan Ikhlas A IA

Future medicinal chemistry 20180523 12

<h4>Aim</h4>There is little information available on the monoamine oxidase isoform selectivity of N-alkyl harmine analogs, which exhibit a myriad of activities including MAO-A, DYRK1A and cytotoxicity to several select cancer cell lines.<h4>Results</h4>Compounds 3e and 4c exhibited an IC<sub>50</sub> of 0.83 ± 0.03 and 0.43 ± 0.002 μM against MAO-A and an IC<sub>50</sub> of 0.26 ± 0.04 and 0.36 ± 0.001 μM against MAO-B, respectively. Molecular docking studies revealed π-π interactions between th ...[more]

PMID: 29788780

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Project description:Background: Methylxanthines including caffeine and theobromine are widely consumed compounds and were recently shown to interact with bovine copper-containing amine oxidase. To the best of our knowledge, no direct demonstration of any interplay between these phytochemicals and human primary amine oxidase (PrAO) has been reported to date. We took advantage of the coexistence of PrAO and monoamine oxidase (MAO) activities in human subcutaneous adipose tissue (hScAT) to test the interaction between several methylxanthines and these enzymes, which are involved in many key pathophysiological processes. Methods: Benzylamine, methylamine, and tyramine were used as substrates for PrAO and MAO in homogenates of subcutaneous adipose depots obtained from overweight women undergoing plastic surgery. Methylxanthines were tested as substrates or inhibitors by fluorimetric determination of hydrogen peroxide, an end-product of amine oxidation. Results: Semicarbazide-sensitive PrAO activity was inhibited by theobromine, caffeine, and isobutylmethylxanthine (IBMX) while theophylline, paraxanthine, and 7-methylxanthine had little effect. Theobromine inhibited PrAO activity by 54% at 2.5 mM. Overall, the relationship between methylxanthine structure and the degree of inhibition was similar to that seen with bovine PrAO, although higher concentrations (mM) were required for inhibition. Theobromine also inhibited oxidation of tyramine by MAO, at the limits of its solubility in a DMSO vehicle. At doses higher than 12 % v/v, DMSO impaired MAO activity. MAO was also inhibited by millimolar doses of IBMX, caffeine and by other methylxanthines to a lesser extent. Conclusions: This preclinical study extrapolates previous findings with bovine PrAO to human tissues. Given that PrAO is a potential target for anti-inflammatory drugs, it indicates that alongside phosphodiesterase inhibition and adenosine receptor antagonism, PrAO and MAO inhibition could contribute to the health benefits of methylxanthines, especially their anti-inflammatory effects.

Dataset Information

Isoform selectivity of harmine-conjugated 1,2,3-triazoles against human monoamine oxidase.

Publications

Isoform selectivity of harmine-conjugated 1,2,3-triazoles against human monoamine oxidase.

Similar Datasets

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