Title:Design and Synthesis of Tetrahydroisoquinoline Derivatives as Anti-Angiogenesis and Anti-Cancer Agents
Volume: 21
Issue: 18
Author(s): Madhavi Gangapuram, Suresh Eyunni, Wang Zhang and Kinfe K. Redda*
Affiliation:
- College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, Florida 32307,United States
Keywords:
Tetrahydroisoquinoline derivatives (THIQs), KRas, colon cancer, anti-angiogenesis, molecular docking, phenyl ring (GM-3-18).
Abstract:
Aim: The aim of our research work is the synthesis of tetrahydroisoquinoline derivatives as anti-Angiogenesis
and anti-cancer agents.
Background: Cancer is the second leading cause of deaths in the United States. The current recovery rate from
the advanced treatment for the cancer is excessively low. Therefore, the identification of novel, potent, and less
toxic anticancer agents remains a top priority.
Objective: To evaluate anti-angiogenesis and 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.
and to carry out 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 VEGF receptors.
Results: Compound GM-3-18 was found to possess significant activities for KRas inhibition, with IC50 values
in the range 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-position of the phenyl ring (GM-3-18) exhibited significant
KRas inhibition against all colon cancer cell lines.
