期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 4, 页码 1902-1916出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01386
关键词
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资金
- CNRS, Universite Paris-Sud
- La Ligue Nationale Contre le Cancer through an Equipe Labellisee 2014 grant
- Agence Nationale de la Recherche [ANR-10-LABX-33]
- LABX LERMIT
- Fondation ARC pour la recherche sur le cancer
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.
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