title: 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.affiliation: School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK.
authors.forename: Marcella
authors.initials: M
authors.lastname: Bassetto
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK. Electronic address: Ferlas1@cardiff.ac.uk.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Ferla
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pertusati
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK.
authors.forename: Sahar
authors.initials: S
authors.lastname: Kandil
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Westwell
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
mesh_terms: D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001549:Benzamides; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010539:Permeability; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D011487:Protein Conformation; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism; D014105:Tosyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D010669:Phenylthiohydantoin; C540278:enzalutamide; C053541:bicalutamide
keywords: Androgen receptor; Antiproliferative activity; Bicalutamide; Enzalutamide; Perfluoroalkyl; Prostate cancer