College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, Florida 32307, United States.
Department of Chemistry, College of Science and Technology, Florida A&M University, Tallahassee, Florida 32307, United States.
Anticancer Agents Med Chem. 2021;21(18):2505-2511. doi: 10.2174/1871520621666210112122913.
The aim of our research work is the synthesis of tetrahydroisoquinoline derivatives as anti-Angiogenesis and anti-cancer agents.
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.
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.
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.
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).
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.
我们的研究工作旨在合成四氢异喹啉衍生物作为抗血管生成和抗癌药物。
癌症是美国第二大致死原因。目前，癌症晚期治疗的康复率极低。因此，识别新型、有效且毒性较小的抗癌药物仍然是当务之急。
评估 THIQs 在不同结直肠癌细胞系（CRC）即 Colo320、DLD-1、HCT116、SNU-C1、SW480 和 GSK3b 中的抗血管生成和抗癌活性，以及在预处理的 HCT116 基础活力中进行 THIQs 的分子对接研究。
在 Lilly 的开放式创新药物发现计划中筛选了 20 种合成的 THIQs，并选择了 12 种化合物用于在不同结直肠癌细胞系的 KRas（Kirsten 大鼠肉瘤）-Wnt SL（合成致死）基础活力中进行体外初步筛选。我们实验室还对活性 THIQs 进行了对接研究，针对 KRas 和 VEGF 受体的活性部位。
发现化合物 GM-3-18 对所有结直肠癌细胞系的 KRas 抑制具有显著活性，IC50 值在 0.9 μM 至 10.7 μM 范围内。化合物 GM-3-121 表现出有效的抗血管生成活性，IC50 = 1.72 μM。分子对接研究表明，GM-3-18 和 GM-3-121 的羰基氧原子与 THR 74（A）的-OH 基团的氢形成氢键相互作用。
结果表明，所有化合物对 KRas 抑制均表现出中等至高度活性。在苯环的 4-位带有氯原子的 THIQs（GM-3-18）对所有结直肠癌细胞系均表现出显著的 KRas 抑制作用。
