A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF5) and pentafluoroethyl (C2F5) substituents: Improved antiproliferative agents against prostate cancer

Fabrizio Pertusati; Salvatore Ferla; Marcella Bassetto; Andrea Brancale; Sahar Khandil; Andrew D Westwell; Christopher McGuigan

doi:10.1016/j.ejmech.2019.07.001

A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF₅) and pentafluoroethyl (C₂F₅) substituents: Improved antiproliferative agents against prostate cancer

Eur J Med Chem. 2019 Oct 15:180:1-14. doi: 10.1016/j.ejmech.2019.07.001. Epub 2019 Jul 3.

Authors

Fabrizio Pertusati¹, Salvatore Ferla², Marcella Bassetto², Andrea Brancale², Sahar Khandil², Andrew D Westwell², Christopher McGuigan²

Affiliations

¹ School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edwards VII Avenue, CF10 3NB, Cardiff, Wales, UK. Electronic address: pertusatif1@cardiff.ac.uk.
² School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edwards VII Avenue, CF10 3NB, Cardiff, Wales, UK.

PMID: 31288149
DOI: 10.1016/j.ejmech.2019.07.001

Abstract

SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC₅₀ values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145 and 22Rv1), showing up to 48-fold increase in comparison with the parent structures. In particular, SF₅ enobosarm analogues were found to be most potent compounds, full AR antagonists and with favourable ADME properties. The most promising compound (48a) was evaluated for its in vivo efficacy in PC xenograft mouse model (22Rv1) with results comparable to the standard-of-care docetaxel.

Keywords: Androgen receptor; Antiproliferative activity; Bicalutamide; Enobosarm; Enzalutamide; Pentafluoroethyl; Pentafluorosulfanyl; Prostate cancer.

MeSH terms

Anilides / chemical synthesis
Anilides / chemistry
Anilides / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzamides
CHO Cells
Cell Line, Tumor
Cell Proliferation / drug effects
Cricetulus
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Ether-A-Go-Go Potassium Channels / metabolism
Humans
Hydrocarbons, Fluorinated / chemistry
Hydrocarbons, Fluorinated / pharmacology
Male
Mice
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Nitriles / chemical synthesis
Nitriles / chemistry
Nitriles / pharmacology*
Phenylthiohydantoin / analogs & derivatives*
Phenylthiohydantoin / chemical synthesis
Phenylthiohydantoin / chemistry
Phenylthiohydantoin / pharmacology
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / pathology
Structure-Activity Relationship
Sulfhydryl Compounds / chemistry
Sulfhydryl Compounds / pharmacology
Tosyl Compounds / chemical synthesis
Tosyl Compounds / chemistry
Tosyl Compounds / pharmacology*

Substances

Anilides
Antineoplastic Agents
Benzamides
Ether-A-Go-Go Potassium Channels
Hydrocarbons, Fluorinated
Nitriles
Sulfhydryl Compounds
Tosyl Compounds
Phenylthiohydantoin
enzalutamide
bicalutamide
ostarine