Discovery of Fused Isoquinolinone/Triazole as a Scaffold for Tankyrase and PARP Inhibition

A series of fused
isoquinolinone/triazole hybrids were designed
and prepared applying a unified versatile synthetic strategy. This
practically involved three steps, a novel one-pot CuAAc “click”
reaction-iodination process, an amidation and a copper-catalyzed intramolecular
Ullmann cyclization and was found to be applicable for a variety of
substitutions patterns on the main framework. Some of those synthesized
hybrids were tested for selected ADP-ribosyltransferases and found
to display nanomolar potency against TNKS2, whereas selectivity was
also observed in comparison to other tested PARPs. The SAR studies
divulged key structural features which are responsible for this selectivity.
Moreover, the identification of the binding site of those selective
derivatives using X-ray crystallography revealed that they are accommodated
in the nicotinamide binding subsite while certain groups extend toward
a hydrophobic pocket unique to tankyrases.