RESUMEN
Recently, we have shown that harmine induces ß-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 ß-cell proliferation based on our related previous structure-activity relationship studies of harmine in the context of diabetes and ß-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 ß-cell proliferation capability. The DYRK1A inhibitor, compound 1-2b, induced ß-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 ß-cell proliferation and cell-specific targeting approach for diabetes therapeutics.