2. Academic Validation
  3. 1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin-Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation

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

  • J Med Chem. 2019 Feb 28;62(4):1902-1916. doi: 10.1021/acs.jmedchem.8b01386.
Timothée Naret 1,  Ilhem Khelifi 1,  Olivier Provot 1,  Jérôme Bignon 2,  Hélène Levaique 2,  Joelle Dubois 3,  Martin Souce 4,  Athena Kasselouri 4,  Alain Deroussent 5,  Angélo Paci 5 6,  Paloma F Varela 7,  Benoît Gigant 7,  Mouad Alami 1,  Abdallah Hamze 1
Affiliations

Affiliations

  • 1 BioCIS, Université Paris-Sud, CNRS, Équipe Labellisée Ligue Contre le Cancer , Université Paris-Saclay , F-92290 Châtenay-Malabry , France.
  • 2 CIBI Plateform , Institut de Chimie des Substances Naturelles, UPR 2301, CNRS , F-91198 Gif sur Yvette , France.
  • 3 Institut de Chimie des Substances Naturelles, UPR 2301, CNRS , F-91198 Gif sur Yvette , France.
  • 4 Lip(Sys)2, Chimie Analytique Pharmaceutique (FKA EA4041 Groupe de Chimie Analytique de Paris-Sud), Université Paris-Sud , Université Paris-Saclay , F-92290 Châtenay-Malabry , France.
  • 5 UMR 8203, Laboratoire de Vectorologie et Thérapeutique Anticancéreuses, CNRS, Université Paris-Sud , Université Paris-Saclay, Gustave Roussy , F-94805 Villejuif , France.
  • 6 Department of Pharmacology and Drug Analysis, Gustave Roussy Cancer Campus Grand Paris , Université Paris-Sud , F-94805 Villejuif , France.
  • 7 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS , Université Paris-Sud, Université Paris-Saclay , F-91198 Gif-sur-Yvette , France.
PMID: 30525602 DOI: 10.1021/acs.jmedchem.8b01386
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 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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