Synthesis and biological activity of 1H-pyrrolo[3,2-g]isoquinolines as Haspin kinase inhibitors

Based on previous results, new 1H-pyrrolo[3,2-g]isoquinolines were synthesized and evaluated for their ability to inhibit Haspin. Considering that analogues methylated at the indole nitrogen could retain their Haspin inhibitory potency, conjugates that could be suitable for a use in a PROTAC approach were prepared by N-alkylation. In addition, based on the Haspin inhibitory potency of 1H-pyrrolo[3,2-g]isoquinoline-3-carbaldehyde analogue, an additional PROTAC candidate was synthesized by carbonylation at the 3-position. Unfortunately, none of these conjugates exhibited Haspin inhibitory potency. Nevertheless, N-methylated derivative 10 bearing a pyridin-4-yl substituent at the 3-position is the best selective Haspin inhibitor identified to date in these series, with an IC₅₀ value of 23.6 nM and a selectivity index superior to 14 compared to other protein kinases tested. Additionally, this compound showed both interesting effects on cell viability of various human cell lines and significant inhibitory properties on cellular Haspin kinase.