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

Recently, we have shown that harmine induces &beta
cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. We explore structure&ndash
activity relationships of the 7-position of harmine for both DYRK1A kinase inhibition and &beta
cell proliferation based on our related previous structure&ndash
activity relationship studies of harmine in the context of diabetes and &beta
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 &beta
cell proliferation capability. The DYRK1A inhibitor, compound 1-2b, induced &beta
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 &beta
cell proliferation and cell-specific targeting approach for diabetes therapeutics.