A single-step synthesis of 5,6-dihydropyrrolo[2,1-a]isoquinolines and evaluation of their anti-leukemic activity

While a pharmaceutically intriguing scaffold, 5,6-dihydropyrrolo[2,1-a]isoquinoline (DHPIQ), has precedently been prepared from diverse tetrahydroisoquinolines (THIQs) using elaborate conditions, convenient metal-free methods were discovered from condensation of cyanomethylene-THIQ (1) and α-halo-ketones or aldehydes (1a) to afford 15 DHPIQs (2–16) in moderate yields by employing unique reactivities of the secondary amine and α-carbon to the nitrile of 1. Preliminary biological studies with chronic myelogenous leukemia K562 and adriamycin-resistant K562 (K562/ADM) cells exhibited some of the DHPIQs tested were active in the both cell lines. In particular, cyclohexyl-fused DHPIQ (10) showed GI₅₀ values of 9.79 and 13.60 μM in K562 and K562/ADM cells, respectively. Based on the flow cytometry analysis of 10, the anti-cancer activity could be from apoptosis-related mechanisms. Overall, this DHPIQ scaffold may be further optimized to discover clinically meaningful anti-leukemic agents overcoming adriamycin resistance.