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Development of β-amino-carbonyl compounds as androgen receptor antagonists.

Zhang ZY, Zhu YH, Zhou CH, Liu Q, Lu HL, Ge YJ, Wang MW - Acta Pharmacol. Sin. (2014)

Bottom Line: The therapeutic effects on tumor growth in vivo were observed in male SCID mice bearing LNCaP xenografts.Further structural modifications led to the discovery of a androgen receptor antagonist (compound 6012), which blocked androgen receptor nuclear translocation, androgen-responsive gene expression and androgen-dependent LNCaP cell proliferation.The pharmacological effects of 6012, including AR binding, androgen-induced AR translocation, NH2- and COOH-terminal interaction, growth inhibition of LNCaP cells in vitro and LNCaP xenograft growth in nude mice, were mainly restricted to isomer 6012-4 (1R, 3S).

View Article: PubMed Central - PubMed

Affiliation: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.

ABSTRACT

Aim: Androgen receptor (AR) antagonists have proven to be useful in the early control of prostate cancer. The aim of this study was to identify and characterize a novel β-amino-carbonyl-based androgen receptor antagonist.

Methods: Different isomers of the β-amino-carbonyl compounds were obtained by chiral separation. The bioactivities of the isomers were evaluated by AR nuclear translocation, mammalian two-hybrid, competitive receptor binding and cell proliferation assays. The expression of genes downstream of AR was analyzed with real-time PCR. The therapeutic effects on tumor growth in vivo were observed in male SCID mice bearing LNCaP xenografts.

Results: Compound 21 was previously identified as an AR modulator by the high-throughput screening of a diverse compound library. In the present study, the two isomers of compound 21, termed compounds 21-1 and 21-2, were characterized as partial AR agonists in terms of androgen-induced AR nuclear translocation, prostate-specific antigen expression and cell proliferation. Further structural modifications led to the discovery of a androgen receptor antagonist (compound 6012), which blocked androgen receptor nuclear translocation, androgen-responsive gene expression and androgen-dependent LNCaP cell proliferation. Four stereoisomers of compound 6012 were isolated, and their bioactivities were assessed. The pharmacological effects of 6012, including AR binding, androgen-induced AR translocation, NH2- and COOH-terminal interaction, growth inhibition of LNCaP cells in vitro and LNCaP xenograft growth in nude mice, were mainly restricted to isomer 6012-4 (1R, 3S).

Conclusion: Compound 6012-4 was determined to be a novel androgen receptor antagonist with prostate cancer inhibitory activities comparable to bicalutamide both in vitro and in vivo.

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Molecular modeling of isomer 6012-4 to androgen receptor. (A) The structure of isomer 6012-4. (B) Isomer 6012-4 is docked in the androgen receptor binding domain (2AXA). (C) Binding position of selective androgen receptor modulator S1 in the androgen receptor ligand-binding domain (AR-LBD) (2AXA). (D) Predicted binding position of isomer 6012-4 in AR-LBD. The shaded ellipse indicates the location of the androgen receptor active function 2 (AF2) domain.
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fig5: Molecular modeling of isomer 6012-4 to androgen receptor. (A) The structure of isomer 6012-4. (B) Isomer 6012-4 is docked in the androgen receptor binding domain (2AXA). (C) Binding position of selective androgen receptor modulator S1 in the androgen receptor ligand-binding domain (AR-LBD) (2AXA). (D) Predicted binding position of isomer 6012-4 in AR-LBD. The shaded ellipse indicates the location of the androgen receptor active function 2 (AF2) domain.

Mentions: Isomers 6012-1, 6012-2, 6012-3, and 6012-4 were separated on a chiral column, and monocrystals were obtained from the mixed solution of ethyl acetate and petroleum ether. Isomer 6012-2 had NMR data similar to isomer 6012-3, whereas isomer 6012-1 had data similar to isomer 6012-4. These results indicate that there are two groups of enantiomers. Finally, the absolute configurations of isomers 6012-2, 6012-3, and 6012-4 were assigned as (1R, 3R), (1S, 3S), and (1R, 3S)-3-[(4-methoxy-2-nitrophenyl)amino]-1-(4-nitrophenyl)-3-phenylpropan-1-ol based on X-ray crystallography (Supplemental Figures 4 and 5). All four isomers docked into AR-LBD (2AXA), and isomer 6012-4 interacted with the androgen-binding groove of the receptor in a way similar to that of the reference AR modulator S1 (Figure 5A). In this binding model, the 4-nitrophenyl group on isomer 6012-4 pointed toward LBD active function 2 (AF2).


Development of β-amino-carbonyl compounds as androgen receptor antagonists.

Zhang ZY, Zhu YH, Zhou CH, Liu Q, Lu HL, Ge YJ, Wang MW - Acta Pharmacol. Sin. (2014)

Molecular modeling of isomer 6012-4 to androgen receptor. (A) The structure of isomer 6012-4. (B) Isomer 6012-4 is docked in the androgen receptor binding domain (2AXA). (C) Binding position of selective androgen receptor modulator S1 in the androgen receptor ligand-binding domain (AR-LBD) (2AXA). (D) Predicted binding position of isomer 6012-4 in AR-LBD. The shaded ellipse indicates the location of the androgen receptor active function 2 (AF2) domain.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4814037&req=5

fig5: Molecular modeling of isomer 6012-4 to androgen receptor. (A) The structure of isomer 6012-4. (B) Isomer 6012-4 is docked in the androgen receptor binding domain (2AXA). (C) Binding position of selective androgen receptor modulator S1 in the androgen receptor ligand-binding domain (AR-LBD) (2AXA). (D) Predicted binding position of isomer 6012-4 in AR-LBD. The shaded ellipse indicates the location of the androgen receptor active function 2 (AF2) domain.
Mentions: Isomers 6012-1, 6012-2, 6012-3, and 6012-4 were separated on a chiral column, and monocrystals were obtained from the mixed solution of ethyl acetate and petroleum ether. Isomer 6012-2 had NMR data similar to isomer 6012-3, whereas isomer 6012-1 had data similar to isomer 6012-4. These results indicate that there are two groups of enantiomers. Finally, the absolute configurations of isomers 6012-2, 6012-3, and 6012-4 were assigned as (1R, 3R), (1S, 3S), and (1R, 3S)-3-[(4-methoxy-2-nitrophenyl)amino]-1-(4-nitrophenyl)-3-phenylpropan-1-ol based on X-ray crystallography (Supplemental Figures 4 and 5). All four isomers docked into AR-LBD (2AXA), and isomer 6012-4 interacted with the androgen-binding groove of the receptor in a way similar to that of the reference AR modulator S1 (Figure 5A). In this binding model, the 4-nitrophenyl group on isomer 6012-4 pointed toward LBD active function 2 (AF2).

Bottom Line: The therapeutic effects on tumor growth in vivo were observed in male SCID mice bearing LNCaP xenografts.Further structural modifications led to the discovery of a androgen receptor antagonist (compound 6012), which blocked androgen receptor nuclear translocation, androgen-responsive gene expression and androgen-dependent LNCaP cell proliferation.The pharmacological effects of 6012, including AR binding, androgen-induced AR translocation, NH2- and COOH-terminal interaction, growth inhibition of LNCaP cells in vitro and LNCaP xenograft growth in nude mice, were mainly restricted to isomer 6012-4 (1R, 3S).

View Article: PubMed Central - PubMed

Affiliation: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.

ABSTRACT

Aim: Androgen receptor (AR) antagonists have proven to be useful in the early control of prostate cancer. The aim of this study was to identify and characterize a novel β-amino-carbonyl-based androgen receptor antagonist.

Methods: Different isomers of the β-amino-carbonyl compounds were obtained by chiral separation. The bioactivities of the isomers were evaluated by AR nuclear translocation, mammalian two-hybrid, competitive receptor binding and cell proliferation assays. The expression of genes downstream of AR was analyzed with real-time PCR. The therapeutic effects on tumor growth in vivo were observed in male SCID mice bearing LNCaP xenografts.

Results: Compound 21 was previously identified as an AR modulator by the high-throughput screening of a diverse compound library. In the present study, the two isomers of compound 21, termed compounds 21-1 and 21-2, were characterized as partial AR agonists in terms of androgen-induced AR nuclear translocation, prostate-specific antigen expression and cell proliferation. Further structural modifications led to the discovery of a androgen receptor antagonist (compound 6012), which blocked androgen receptor nuclear translocation, androgen-responsive gene expression and androgen-dependent LNCaP cell proliferation. Four stereoisomers of compound 6012 were isolated, and their bioactivities were assessed. The pharmacological effects of 6012, including AR binding, androgen-induced AR translocation, NH2- and COOH-terminal interaction, growth inhibition of LNCaP cells in vitro and LNCaP xenograft growth in nude mice, were mainly restricted to isomer 6012-4 (1R, 3S).

Conclusion: Compound 6012-4 was determined to be a novel androgen receptor antagonist with prostate cancer inhibitory activities comparable to bicalutamide both in vitro and in vivo.

Show MeSH
Related in: MedlinePlus