Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor

Yali He, Donghua Yin, Minoli Perera, Leonid Kirkovsky, Nina Stourman, Wei Li, James T. Dalton, Duane Miller

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

While nonsteroidal androgen receptor (AR) antagonists have been known for many years, and used in the clinic for the treatment of hormone dependent prostate cancer, very little is known about nonsteroidal AR agonists. We designed and synthesized a series of chiral bicalutamide analogs, which bear electron-withdrawing groups (either a cyano or a nitro group at the 4-position and a trifluoromethyl group at the 3-position) in the aromatic A ring, and different substituents at the para position in the aromatic B ring of the parent molecule. We also synthesized a series of racemic bicalutamide analogs, which have a trifluoromethyl group instead of a methyl group at the R2 position. We examined AR binding affinities of our compounds in a competitive binding assay with a radiolabeled high affinity AR ligand, 3H-mibolerone, and also measured their abilities to stimulate AR-mediated transcriptional activation in a cotransfection assay. These studies demonstrated that (1) nonsteroidal ligands can be structurally modified from known nonsteroidal antiandrogens to generate ligands capable of activating AR-mediated transcriptional activation. (2) R-isomer analogs exhibit higher AR binding affinity and more potent functional activity than their corresponding S-isomers in all cases. (3) All sulphide analogs show higher AR binding affinity and more potent functional activity than their corresponding sulphone analogs, with the exception of ligand R-8. Those ligands which exhibit high AR binding affinity and potent functional activity for human AR may provide effective clinical uses for male fertility, male contraception, and hormone replacement therapy.

Original languageEnglish (US)
Pages (from-to)619-634
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume37
Issue number8
DOIs
StatePublished - Jul 31 2002

Fingerprint

Androgen Receptors
Ligands
Isomers
Transcriptional Activation
Assays
Nonsteroidal Anti-Androgens
Androgen Receptor Antagonists
Chemical activation
Hormones
Sulfones
Competitive Binding
Hormone Replacement Therapy
Sulfides
Contraception
Androgens
Fertility
Prostatic Neoplasms
Electrons
Molecules

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor. / He, Yali; Yin, Donghua; Perera, Minoli; Kirkovsky, Leonid; Stourman, Nina; Li, Wei; Dalton, James T.; Miller, Duane.

In: European Journal of Medicinal Chemistry, Vol. 37, No. 8, 31.07.2002, p. 619-634.

Research output: Contribution to journalArticle

He, Yali ; Yin, Donghua ; Perera, Minoli ; Kirkovsky, Leonid ; Stourman, Nina ; Li, Wei ; Dalton, James T. ; Miller, Duane. / Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor. In: European Journal of Medicinal Chemistry. 2002 ; Vol. 37, No. 8. pp. 619-634.
@article{90cb6e7dffa94dc983de0263c198e9f9,
title = "Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor",
abstract = "While nonsteroidal androgen receptor (AR) antagonists have been known for many years, and used in the clinic for the treatment of hormone dependent prostate cancer, very little is known about nonsteroidal AR agonists. We designed and synthesized a series of chiral bicalutamide analogs, which bear electron-withdrawing groups (either a cyano or a nitro group at the 4-position and a trifluoromethyl group at the 3-position) in the aromatic A ring, and different substituents at the para position in the aromatic B ring of the parent molecule. We also synthesized a series of racemic bicalutamide analogs, which have a trifluoromethyl group instead of a methyl group at the R2 position. We examined AR binding affinities of our compounds in a competitive binding assay with a radiolabeled high affinity AR ligand, 3H-mibolerone, and also measured their abilities to stimulate AR-mediated transcriptional activation in a cotransfection assay. These studies demonstrated that (1) nonsteroidal ligands can be structurally modified from known nonsteroidal antiandrogens to generate ligands capable of activating AR-mediated transcriptional activation. (2) R-isomer analogs exhibit higher AR binding affinity and more potent functional activity than their corresponding S-isomers in all cases. (3) All sulphide analogs show higher AR binding affinity and more potent functional activity than their corresponding sulphone analogs, with the exception of ligand R-8. Those ligands which exhibit high AR binding affinity and potent functional activity for human AR may provide effective clinical uses for male fertility, male contraception, and hormone replacement therapy.",
author = "Yali He and Donghua Yin and Minoli Perera and Leonid Kirkovsky and Nina Stourman and Wei Li and Dalton, {James T.} and Duane Miller",
year = "2002",
month = "7",
day = "31",
doi = "10.1016/S0223-5234(02)01335-1",
language = "English (US)",
volume = "37",
pages = "619--634",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",
number = "8",

}

TY - JOUR

T1 - Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor

AU - He, Yali

AU - Yin, Donghua

AU - Perera, Minoli

AU - Kirkovsky, Leonid

AU - Stourman, Nina

AU - Li, Wei

AU - Dalton, James T.

AU - Miller, Duane

PY - 2002/7/31

Y1 - 2002/7/31

N2 - While nonsteroidal androgen receptor (AR) antagonists have been known for many years, and used in the clinic for the treatment of hormone dependent prostate cancer, very little is known about nonsteroidal AR agonists. We designed and synthesized a series of chiral bicalutamide analogs, which bear electron-withdrawing groups (either a cyano or a nitro group at the 4-position and a trifluoromethyl group at the 3-position) in the aromatic A ring, and different substituents at the para position in the aromatic B ring of the parent molecule. We also synthesized a series of racemic bicalutamide analogs, which have a trifluoromethyl group instead of a methyl group at the R2 position. We examined AR binding affinities of our compounds in a competitive binding assay with a radiolabeled high affinity AR ligand, 3H-mibolerone, and also measured their abilities to stimulate AR-mediated transcriptional activation in a cotransfection assay. These studies demonstrated that (1) nonsteroidal ligands can be structurally modified from known nonsteroidal antiandrogens to generate ligands capable of activating AR-mediated transcriptional activation. (2) R-isomer analogs exhibit higher AR binding affinity and more potent functional activity than their corresponding S-isomers in all cases. (3) All sulphide analogs show higher AR binding affinity and more potent functional activity than their corresponding sulphone analogs, with the exception of ligand R-8. Those ligands which exhibit high AR binding affinity and potent functional activity for human AR may provide effective clinical uses for male fertility, male contraception, and hormone replacement therapy.

AB - While nonsteroidal androgen receptor (AR) antagonists have been known for many years, and used in the clinic for the treatment of hormone dependent prostate cancer, very little is known about nonsteroidal AR agonists. We designed and synthesized a series of chiral bicalutamide analogs, which bear electron-withdrawing groups (either a cyano or a nitro group at the 4-position and a trifluoromethyl group at the 3-position) in the aromatic A ring, and different substituents at the para position in the aromatic B ring of the parent molecule. We also synthesized a series of racemic bicalutamide analogs, which have a trifluoromethyl group instead of a methyl group at the R2 position. We examined AR binding affinities of our compounds in a competitive binding assay with a radiolabeled high affinity AR ligand, 3H-mibolerone, and also measured their abilities to stimulate AR-mediated transcriptional activation in a cotransfection assay. These studies demonstrated that (1) nonsteroidal ligands can be structurally modified from known nonsteroidal antiandrogens to generate ligands capable of activating AR-mediated transcriptional activation. (2) R-isomer analogs exhibit higher AR binding affinity and more potent functional activity than their corresponding S-isomers in all cases. (3) All sulphide analogs show higher AR binding affinity and more potent functional activity than their corresponding sulphone analogs, with the exception of ligand R-8. Those ligands which exhibit high AR binding affinity and potent functional activity for human AR may provide effective clinical uses for male fertility, male contraception, and hormone replacement therapy.

UR - http://www.scopus.com/inward/record.url?scp=0037205938&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037205938&partnerID=8YFLogxK

U2 - 10.1016/S0223-5234(02)01335-1

DO - 10.1016/S0223-5234(02)01335-1

M3 - Article

VL - 37

SP - 619

EP - 634

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

IS - 8

ER -