Chiral nonsteroidal affinity ligands for the androgen receptor. 1. Bicalutamide analogues bearing electrophilic groups in the B aromatic ring.
A series of chiral analogues of bicalutamide bearing electrophilic groups (isothiocyanate, N-chloroacetyl, and N-bromoacetyl) on aromatic ring B of the parent molecule were synthesized. These compounds were designed as affinity ligands for the androgen receptor (AR). We prepared the (R)- and (S)-optical isomers of these compounds as pure enantiomers. The AR binding affinities of these compounds were measured in a competitive binding assay with the radiolabeled high-affinity AR ligand, [(3)H]mibolerone. In accordance with our previous results for the enantiomers of bicalutamide, we found that all (R)-isomers demonstrated much higher binding affinity to the AR as compared to their corresponding (S)-isomers. The para-substituted affinity ligands in ring B bound the AR with higher affinities than the corresponding meta-substituted analogues. Oxidation of thioester affinity ligands to their sulfonyl analogues for the para-substituted compounds decreased AR binding affinities and similar modification increased binding affinities for corresponding meta-analogues. The least potent para-substituted sulfonyl compounds had higher AR binding affinities than the most potent meta-substituted sulfonyl compounds. Overall, the para-substituted unoxidized molecules demonstrated the highest AR binding affinity. Subsequent research using AR exchange assays and Scatchard analyses showed that the isothiocyanate affinity ligands (R)-7, (R)-9, and (R)-10 reported herein are the first specific chemoaffinity ligands for the AR.
Kirkovsky
L
L
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee-Memphis, Memphis, Tennessee 38163, USA.
Mukherjee
A
A
Yin
D
D
Dalton
J T
JT
Miller
D D
DD
D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D004220:Disulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D017879:Isothiocyanates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008297:Male; D009570:Nitriles; D011467:Prostate / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014105:Tosyl Compounds
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D004220:Disulfides; D017879:Isothiocyanates; D008024:Ligands; C405040:N1-(4-cyano--3-(trifluoromethyl)phenyl)-2-hydroxy-3-((3-isothiocyanatophenyl)sulfanyl)-2-methylpropanamide; C405038:N1-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-((4-isothiocyanatophenyl)sulfanyl)-2-methylpropanamide; C405039:N1-(4-cyano-3--(trifluoromethyl)phenyl)-2-hydroxy-3-((4-isothiocyanatophenyl)sulfonyl)-2-methylpropanamide; D009570:Nitriles; D011944:Receptors, Androgen; D013450:Sulfones; D014105:Tosyl Compounds; C053541:bicalutamide