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

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.

• Authors: Fabrizio Pertusati, Salvatore Ferla, Marcella Bassetto, Andrea Brancale, Sahar Khandil, Andrew D Westwell, Christopher McGuigan
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 180 Pg. 1-14 (Oct 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 31288149 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier Masson SAS.

Chemical References

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

Topics

• Anilides (chemical synthesis, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, 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, metabolism)
• Humans
• Hydrocarbons, Fluorinated (chemistry, pharmacology)
• Male
• Mice
• Mice, Nude
• Molecular Structure
• Neoplasms, Experimental (drug therapy, pathology)
• Nitriles (chemical synthesis, chemistry, pharmacology)
• Phenylthiohydantoin (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Prostatic Neoplasms (drug therapy, pathology)
• Structure-Activity Relationship
• Sulfhydryl Compounds (chemistry, pharmacology)
• Tosyl Compounds (chemical synthesis, chemistry, pharmacology)