Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation

Kunal Kumar,Roberto Sanchez,Robert J Devita,Peng Wang,Cody Secor,Ethan A Swartz,Susmita Khamrui,Michael B Lazarus,Andrew F Stewart

doi:10.3390/molecules25081983

Kunal Kumar, Roberto Sanchez + Show 7 more

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https://doi.org/10.3390/molecules25081983

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Abstract

Recently, we have shown that harmine induces β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. We explore structure–activity relationships of the 7-position of harmine for both DYRK1A kinase inhibition and β-cell proliferation based on our related previous structure–activity relationship studies of harmine in the context of diabetes and β-cell specific targeting strategies. 33 harmine analogs of the 7-position substituent were synthesized and evaluated for biological activity. Two novel inhibitors were identified which showed DYRK1A inhibition and human β-cell proliferation capability. The DYRK1A inhibitor, compound 1-2b, induced β-cell proliferation half that of harmine at three times higher concentration. From these studies we can draw the inference that 7-position modification is limited for further harmine optimization focused on β-cell proliferation and cell-specific targeting approach for diabetes therapeutics.

Highlights

The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a eukaryotic protein kinase that has been shown to play important roles in biological processes related to various diseases [1,2,3,4] and more recently, as a major regulator of human insulin-producing pancreatic β-cells [5,6,7,8]
We have reported our efforts to study the harmine 7-position with the objective to identify novel harmine-based DYRK1A inhibitors with human β-cell proliferation activity and chemical potential for targeted delivery
We developed chemistry to carry out modifications of the 7-position of harmine by introducing substituents bearing terminal methyl ester, carboxamide, carboxylic acid and amino/substituted amino groups with chain lengths varying from 1–5 carbons

Summary

Introduction

The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a eukaryotic protein kinase that has been shown to play important roles in biological processes related to various diseases [1,2,3,4] and more recently, as a major regulator of human insulin-producing pancreatic β-cells [5,6,7,8]. Our group found that harmine is able to induce human β-cell proliferation and DYRK1A-NFAT pathway as being the major pathway for this cell proliferation [5]. These results have been confirmed in other labs with other DYRK1A inhibitors unrelated to the harmine scaffold, including from our own lab [6,8,34,35,36,37].

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