Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer.

Abstract

Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.

• Authors: Marcella Bassetto, Salvatore Ferla, Fabrizio Pertusati, Sahar Kandil, Andrew D Westwell, Andrea Brancale, Christopher McGuigan
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 118 Pg. 230-43 (Aug 08 2016) ISSN: 1768-3254 [Electronic] France
• PMID: 27131065 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Anilides
• Antineoplastic Agents
• Benzamides
• Nitriles
• Receptors, Androgen
• Tosyl Compounds
• Phenylthiohydantoin
• enzalutamide
• bicalutamide

Topics

• Anilides (chemical synthesis, chemistry, metabolism, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, metabolism, pharmacology)
• Benzamides
• Caco-2 Cells
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chemistry Techniques, Synthetic
• Drug Design
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Male
• Microsomes, Liver (metabolism)
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Nitriles (chemical synthesis, chemistry, metabolism, pharmacology)
• Permeability
• Phenylthiohydantoin (analogs & derivatives, chemical synthesis, chemistry, metabolism, pharmacology)
• Prostatic Neoplasms (pathology)
• Protein Conformation
• Receptors, Androgen (chemistry, metabolism)
• Tosyl Compounds (chemical synthesis, chemistry, metabolism, pharmacology)