Design, synthesis, and anticancer evaluation of novel quinoline derivatives of ursolic acid with hydrazide, oxadiazole, and thiadiazole moieties as potent MEK inhibitors

• Published in: Journal of enzyme inhibition and medicinal chemistry 2019-01, Vol.34 (1), p.955-972
• Main Authors: Jin, Xiao-Yan, Chen, Hao, Li, Dong-Dong, Li, A-Liang, Wang, Wen-Yan, Gu, Wen
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antiproliferative activity; apoptosis; Apoptosis - drug effects; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - metabolism; MEK inhibitor; Membrane Potential, Mitochondrial - drug effects; Models, Molecular; Molecular Structure; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; quinoline; Quinolines - chemistry; Quinolines - pharmacology; Reactive Oxygen Species - metabolism; Research Paper; Structure-Activity Relationship; Thiadiazoles - chemistry; Thiadiazoles - pharmacology; Triterpenes - chemistry; Triterpenes - pharmacology; Ursolic Acid
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2019.1605364

In this article, a series of novel quinoline derivatives of ursolic acid (UA) bearing hydrazide, oxadiazole, or thiadiazole moieties were designed, synthesised, and screened for their in vitro antiproliferative activities against three cancer cell lines (MDA-MB-231, HeLa, and SMMC-7721). A number of compounds showed significant activity against at least one cell line. Among them, compound 4d exhibited the most potent activity against three cancer cell lines with IC 50 values of 0.12 ± 0.01, 0.08 ± 0.01, and 0.34 ± 0.03 μM, respectively. In particular, compound 4d could induce the apoptosis of HeLa cells, arrest cell cycle at the G0/G1 phase, elevate intracellular reactive oxygen species level, and decrease mitochondrial membrane potential. In addition, compound 4d could significantly inhibit MEK1 kinase activity and impede Ras/Raf/MEK/ERK transduction pathway. Therefore, compound 4d may be a potential anticancer agent and a promising lead worthy of further investigation.