Design, synthesis and characterization of potent microtubule inhibitors with dual anti-proliferative and anti-angiogenic activities

• Published in: European journal of medicinal chemistry Vol. 157; pp. 380 - 396
• Main Authors: Zhang, Huijun, Fang, Xiong, Meng, Qian, Mao, Yujia, Xu, Yan, Fan, Tingting, An, Jing, Huang, Ziwei
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.09.2018; Elsevier
• Subjects: Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Anti-angiogenesis; Anti-Proliferation; Apoptosis - drug effects; Cell Cycle Checkpoints - drug effects; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Drug development; Drug Screening Assays, Antitumor; Fused 4-aryl-4H-chromenes; Humans; Life Sciences & Biomedicine; Microtubule inhibitors; Microtubules - drug effects; Molecular Docking Simulation; Molecular Structure; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Tubulin - drug effects; Tubulin - metabolism; Anti-Proliferation; Anti-angiogenesis; Drug development; Fused 4-aryl-4H-chromenes; Microtubule inhibitors; COLCHICINE BINDING-SITE; SERIES; CANCER; APOPTOSIS INDUCERS; DISCOVERY; CHEMOTHERAPY; TUBULIN INHIBITORS; BIOLOGICAL EVALUATION; AGENTS; POLYALKOXY SUBSTITUTED 4H-CHROMENES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.07.043

Microtubule has been an important target for anticancer drug development. Here we report the discovery and characterization of a series of fused 4-aryl-4H-chromene-based derivatives as highly potent microtubule inhibitors. Among a total of 37 derivatives synthesized, 23 exhibited strong in vitro anti-proliferative activities against A375 human melanoma cells. The relationship between the biological activities of these microtubule inhibitors and their chemical structure variations was analyzed. Studies of compounds 27a, 19a and 9a in parallel with colchicine as the positive control compound in a panel of biological assays revealed that these compounds blocked cell cycle progression, increased apoptosis, and inhibited HUVEC capillary tube formation at low nanomolar concentrations. The most potent compound 27a was also tested in eight additional cancer cell lines besides A375 cells and two non-cancer cells and showed potent and selective activity on these cancer cells. To understand the molecular and structure mechanism of action of these compounds, tubulin polymerization and molecular docking studies were carried out for 27a as the representative. The results were consistent with the mechanism by which 27a interacts with the colchicine binding site on tubulin and disrupts tubulin polymerization. With potent dual actions of microtubule destabilization and vascular disruption described above, this small molecule can serve as a valuable research probe of the function and role of microtubules in human diseases and promising lead for developing new therapeutic agents. [Display omitted] •A series of fused 4-aryl-4H-chromene-based derivatives were designed and synthesized.•Biological assays and computational studies were conducted to determine their anti-proliferation and anti-angiogenesis activities and mechanisms of action.•Compound 27a exhibited potent anti-proliferation and anti-angiogenesis activities.