Design and Synthesis of Tetrahydroisoquinoline Derivatives as Anti-Angiogenesis and Anti-Cancer Agents

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.

Keywords: KRas; Tetrahydroisoquinoline derivatives (THIQs); anti-angiogenesis; colon cancer; molecular docking; phenyl ring (GM-3-18)..

Fig. (1).

Tetrahydroisoquinoline analogs tested for KRas and Anti-angiogenesis activity.

Fig. (2).

Anti-angiogenesis activity of compound GM-3-121.

Fig. (3).

Anti-angiogenesis activity of compound GM-3-13.

Fig. (4).

Binding poses of compounds GM-3-18 and GM-3-121 in active site of KRas Receptor.

Fig. (5).

Binding pose of compound GM-3-15 in the active site of KRas Receptor.

Fig. 6.

Binding poses of GM-3-15, GM-3-18 and GM-3-121 in the active site of VEGF Receptor (Bound ligand in the crystal structure for reference (green color)).

Scheme 1.. Reaction Conditions:

(i) H₂O, 90°C, 2h, K₂CO₃, H1; (ii) Dry THF, Et₃N, reflux, 12 h, (iii) NaBH₄, abs EtOH, 0°C, 7h; R = C₆H₅, 4-CH₃-C₆H₄, 4-OCH₃-C₆H₄; 4-Cl-C₆H₄; 4-C₂H₅-C₆H₄. 4-C₃H₇-C₆H₄, 4-C(CH₃)₃-C₆H₄, 4-CF₃-C₆H₄, X = CO, SO₂.