Synthesis and evaluation of new 2-chloro-4-aminopyrimidine and 2,6-dimethyl-4-aminopyrimidine derivatives as tubulin polymerization inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 10; pp. 1769 - 1775
• Main Authors: Xu, Shaoyu, An, Baijiao, Li, Yuxin, Luo, Xunbang, Li, Xingshu, Jia, Xian
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2018
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Design and synthesis; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Mechanism; Microtubules - drug effects; Microtubules - metabolism; Mitochondria - drug effects; Mitochondria - metabolism; Molecular Docking Simulation; Molecular Structure; Polymerization - drug effects; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tubulin polymerization inhibitors; Antiproliferative activity; JTZBPLHBMDEBPB-UHFFFAOYSA-N; Tubulin polymerization inhibitors; Mechanism; Design and synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.04.026

[Display omitted] •Eighteen new MPC-6827 analogues were synthesized and evaluated.•Several compounds exhibited potent antiproliferative activities.•Compound 17 could halt cell cycle progression at the G2/M phase.•Compound 17 could also induce cell apoptosis and mitochondrial dysfunction. Eighteen new 2-chloro-4-aminopyrimidine and 2,6-dimethyl-4-aminopyrimidine derivatives were synthesized and evaluated as tubulin polymerization inhibitor for the treatment of cancer. Among them, compounds 10, 17, 20 and 21 exhibited potent antiproliferative activities against five human cancer cell lines. Microtubule dynamics assay showed that compound 17 could effectively inhibit tubulin polymerization. Molecular docking studies were also carried out to understand the binding pattern. Further mechanism studies revealed that 17 could induce G2/M phase arrest, disrupt the organization of the cellular microtubule network and induce cell apoptosis and mitochondrial dysfunction.