Synthesis of C-glycosyl pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as a scaffold for check point kinase 1 inhibitors.

Indolocarbazole natural products are known to possess a variety of biological activities that hold promise as cancer chemotherapeutic agents. We newly designed C-glycosyl pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione derivatives 7 and 8, which are natural-product-like scaffolds. Compounds 7 and 8 were stereoselectively and efficiently synthesized using β-selective C-allylation, Heck reaction, and thermal 6π-electron cyclization/oxidative aromatization. Their potential as Chk1 inhibitors was investigated, and 7 and 8 exhibited an inhibitory activity with IC50 values of 0.5-9.5 μM, which is good activity for scaffolds. The key intermediate 23 was obtained by five steps from d-ribose in 33% overall yield by this synthetic route, which would enable us to prepare a range of analogues in order to investigate further structure-activity relationship studies in the optimization process.