1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin-Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation

• Published in: Journal of medicinal chemistry 2019-02, Vol.62 (4), p.1902-1916
• Main Authors: Naret, Timothée, Khelifi, Ilhem, Provot, Olivier, Bignon, Jérôme, Levaique, Hélène, Dubois, Joelle, Souce, Martin, Kasselouri, Athena, Deroussent, Alain, Paci, Angélo, Varela, Paloma F, Gigant, Benoît, Alami, Mouad, Hamze, Abdallah
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Biochemistry; Biochemistry, Molecular Biology; Carbazoles - chemical synthesis; Carbazoles - metabolism; Carbazoles - pharmacology; Cell Line, Tumor; Cellular Biology; Chemical Sciences; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints - drug effects; Human Umbilical Vein Endothelial Cells; Humans; Life Sciences; Medicinal Chemistry; Microsomes, Liver - metabolism; Molecular Structure; Polymerization - drug effects; Protein Binding; Quinaldines - chemical synthesis; Quinaldines - metabolism; Quinaldines - pharmacology; Rats; Structural Biology; Structure-Activity Relationship; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - metabolism; Tubulin Modulators - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01386

We report the synthesis and metabolic and biological evaluation of a series of 17 novel heterocyclic derivatives of isocombretastatin-A4 (iso-CA-4) and their structure–activity relationships. Among these derivatives, the most active compound, 4f, inhibited the growth of a panel of seven cancer cell lines with an IC50 in the low nanomolar range. In addition, 4f showed interesting activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. It also induced G2/M cell-cycle arrest. Structural data indicated binding of 4f to the colchicine site of tubulin, likely preventing the curved-to-straight tubulin structural changes that occur during microtubule assembly. Also, 4f disrupted the blood-vessel-like assembly formed by human umbilical-vein endothelial cells in vitro, suggesting its function as a vascular-disrupting agent. An in vitro metabolism study of 4f showed its high human-microsomal stability in comparison with that of iso-CA-4. The physicochemical properties of 4f may be conducive to CNS permeability, suggesting that this compound may be a possible candidate for the treatment of glioblastoma.