title: Arylisothiocyanato selective androgen receptor modulators (SARMs) for prostate cancer.
abstract: A new series of androgen receptor targeted agents (ARTA) was prepared and tested in androgen-dependent and -independent prostate cancer cell lines. These agents were bicalutamide analogs with isothiocyanato substituted B-rings. Also, the linker sulfone of R-bicalutamide was maintained or replaced with several alternative linkages including ether, amine, N-methylamine, thioether, and methylene (in this case the product was a racemic mixture) functional groups at the X-position. To expand the structure-activity relationship (SAR) of these arylisothiocyanato AR ligands, B-ring halogenated arylisothiocyanato ligands were also prepared and tested. The arylisothiocyanato AR ligands showed strong binding affinities to AR ranging from 0.6 to 54 nM. Among them, thioether and ether linkages demonstrated high binding affinities (0.6 and 4.6 nM, respectively) and selective cell growth inhibition (approximately 3- to 6-fold) for LNCaP, an androgen-dependent prostate cancer cell line, when compared to the androgen independent prostate cell lines (DU145, PC-3, and PPC-1) and a bladder cell line (TSU-Pr1). However, the ligands were inactive (IC50>100 mM) in a normal monkey kidney cell line (CV-1) that was used as the control for non-specific toxicity.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Hwang
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Huiping
authors.initials: H
authors.lastname: Xu
authors.forename: Igor M
authors.initials: IM
authors.lastname: Rakov
authors.forename: Michael L
authors.initials: ML
authors.lastname: Mohler
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D000882:Haplorhini; D006801:Humans; D017879:Isothiocyanates / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D012235:Rhodamines; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; D008024:Ligands; D011944:Receptors, Androgen; D012235:Rhodamines; C022027:lissamine rhodamine B