6H9B

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

Summary for 6H9B

• Entry DOI: 10.2210/pdb6h9b/pdb
• Descriptor: Tubulin alpha chain, Tubulin beta chain, Stathmin-4, ... (9 entities in total)
• Functional Keywords: cytoskeleton, cell division, intracellular transport, transport protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 5
• Total formula weight: 214031.09

Authors

Varela, P.F.,Gigant, B. (deposition date: 2018-08-03, release date: 2018-12-19, Last modification date: 2024-01-17)

Primary citation

Naret, T.,Khelifi, I.,Provot, O.,Bignon, J.,Levaique, H.,Dubois, J.,Souce, M.,Kasselouri, A.,Deroussent, A.,Paci, A.,Varela, P.F.,Gigant, B.,Alami, M.,Hamze, A.
1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin-Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation.
J. Med. Chem., 62:1902-1916, 2019

PubMed Abstract: 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 IC 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 G/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.

PubMed: 30525602
DOI: 10.1021/acs.jmedchem.8b01386

Experimental method

X-RAY DIFFRACTION (2.75 Å)