Synthesis and biological evaluation of 1H-pyrrolo[3,2-g]isoquinolines

Abstract

A structure-activity relationship study performed on 1H-pyrrolo[3,2-g]isoquinoline scaffold identified new haspin inhibitors with nanomolar potencies and selectivity indices (SI) over 6 (inhibitory potency evaluated against 8 protein kinases). Compound 22 was the most active of the series (haspin IC₅₀ = 76 nM). Cellular evaluation of 22 confirmed its activity for endogenous haspin in U-2 OS cells and its anti-proliferative activity against various cell lines. In addition, the binding mode of analog 22 in complex with haspin was determined by X-ray crystallography.

Keywords: Cellular activity; Haspin; Indoles; Isoquinolines; Kinase inhibition; Pyrroles.