Design, Synthesis, and Simulation of Functionalized 1,2,3,4‐Tetrahydroisoquinolines to Treat Acute Leukemia Cells

Abstract Tetrahydroisoquinolines (THIQ) are prevalent heterocyclic molecules that are the backbone of several synthetic anticancer compounds and alkaloids showing antitumor activity in melanoma, breast, brain, ovarian, and prostate cancer. We designed and synthesized functionalized THIQ derivatives 7a and 7b and evaluated their anticancer activity using acute myeloid leukemia (AML) cell line, HL‐60 cells. We synthesized these compounds in two steps from functionalized 2 H ‐pyran‐2‐ones. N‐Boc‐protected tetrahydroisoquinolines were synthesized by ring transformation of 6‐aryl‐4‐ sec .amino‐2‐oxo‐2 H ‐pyran‐3‐carbonitriles using N‐Boc‐4‐piperidone in the presence of sodamide in DMSO, then deprotection of the N‐Boc‐protecting group under acidic conditions was carried out to isolate the designed compounds. Compounds 7a and 7b have exhibited the IC 50 values of 10 and 40 µM in vitro studies in the HL‐60, respectively. We found that 7a and 7b induced anti‐leukemic/anticancer activity in HL‐60 cells through interaction with CDK2, cytotoxicity, ROS production, and apoptosis, which may be essential for the new anticancer drug design and further evaluation in AML patients. In silico molecular docking study suggests that compound 7a is preferentially more active than other identified compounds with strong binding affinity to major anticancer receptors. The results of the present study may help design lead compounds with improved activity.