Aim: The aim of our research work is the synthesis of tetrahydroisoquinoline derivatives as anti-Angiogenesis and anti-cancer
Background: Cancer is the second leading cause of deaths in United States. The current recovery rate from the advanced treatment for
the cancer is unacceptably low. Therefore, identification of novel, potent and less toxic anticancer agents remains a top priority.
Objective: To 1) evaluate anti-angiogenesis, anticancer activities of THIQs on different colorectal cancer cell lines (CRC) viz., Colo320,
DLD-1, HCT116, SNU-C1, SW480 and GSK3b in pre-treated viability HCT116. 2) Undertake molecular docking studies of THIQs.
Methods: Twenty synthesized THIQs were screened in the Eli Lilly’s Open Innovation Drug Discovery Program and selected twelve
compounds for in vitro primary screening in the KRas (Kirsten rat sarcoma)-Wnt SL (Synthetic Lethal) in the basal viability of different
colon cancer cell lines. Docking studies of the active THIQs were also performed in our laboratory, targeting the active sites of KRas and
Results: Compound GM-3-18 was found to possess significant activities for KRas inhibition, with IC50 values in the rage of 0.9 µM to
10.7 µM, for all colon cancer cell lines. Compound GM-3-121 showed potent anti-angiogenesis activity with IC50 = 1.72 µM. Molecular
docking studies showed that the carbonyl oxygen atoms of GM-3-18 and GM-3-121 showed hydrogen bonding interactions with the
hydrogen of - OH groups of THR 74 (A).
Conclusion: The results indicated that all the compounds showed moderate to high activity for KRas inhibition. The THIQs bearing the
chloro group at the 4-postiton of the phenyl ring (GM-3-18) exhibited significant KRas inhibition against all colon cancer cell lines.