Design, synthesis, and structure–activity relationships of novel 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents

• Published in: European journal of medicinal chemistry Vol. 69; pp. 77 - 89
• Main Authors: Tang, Qidong, Zhao, Yanfang, Du, Xinming, Chong, Lian'e, Gong, Ping, Guo, Chun
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.11.2013; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; c-Met; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; HT29 Cells; Humans; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - metabolism; Quinoline derivatives; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Science & Technology; Structure-Activity Relationship; Synthesis; Quinoline derivatives; c-Met; Synthesis; Antiproliferative activity; ANGIOGENESIS; ANALOGS; INHIBITOR; CANCER; DISCOVERY
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.08.019

Two series of quinoline derivatives bearing the pyridine/pyrimidine scaffold were synthesized, and evaluated for their c-Met kinase inhibitory activity and antiproliferative activity against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) were evaluated in vitro. Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 18b (c-Met half-maximal inhibitory concentration [IC50] = 1.39 nM) showed a 7.3-fold increase in activity against HT-29 cell line in vitro. Structure–activity relationship studies indicated that regulation of the electron density on the pyridine/pyrimidine ring to a proper degree was a key factor in improving the antitumor activity. [Display omitted] Two series of quinoline derivatives bearing pyridine/pyrimidine scaffolds were synthesized and evaluated for their cytotoxic activities. Seven potent compounds were further examined for their c-Met kinase activity. •Two series of quinoline derivatives were designed and synthesized.•The target compounds showed potent antitumor activity.•Seven compounds were further examined for their c-Met kinase activity.•The cytotoxicity of 18b was 7.3-fold higher against HT-29 cells than foretinib.•Compound 18b showed an IC50 value of 1.39 nM against c-Met kinase.