Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists

Satoshi Yamamoto; Nobuyuki Matsunaga; Takenori Hitaka; Masami Yamada; Takahito Hara; Junichi Miyazaki; Takashi Santou; Masami Kusaka; Masuo Yamaoka; Naoyuki Kanzaki; Shuichi Furuya; Akihiro Tasaka; Kazumasa Hamamura; Mitsuhiro Ito

doi:10.1016/j.bmc.2011.10.067

Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists

Satoshi Yamamoto, Nobuyuki Matsunaga, Takenori Hitaka, Masami Yamada, Takahito Hara, Junichi Miyazaki, Takashi Santou, Masami Kusaka, Masuo Yamaoka, Naoyuki Kanzaki, Shuichi Furuya, Akihiro Tasaka, Kazumasa Hamamura, Mitsuhiro Ito

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

Abstract

A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5- (hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3- carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.

Original language	English
Pages (from-to)	422-434
Number of pages	13
Journal	Bioorganic and Medicinal Chemistry
Volume	20
Issue number	1
DOIs	https://doi.org/10.1016/j.bmc.2011.10.067
Publication status	Published - Jan 1 2012
Externally published	Yes

Keywords

1-Arylmethyl-4-phenylpyrrole derivatives
Androgen receptor antagonists
Castration-resistant prostate cancers

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmc.2011.10.067

Cite this

Yamamoto, S., Matsunaga, N., Hitaka, T., Yamada, M., Hara, T., Miyazaki, J., Santou, T., Kusaka, M., Yamaoka, M., Kanzaki, N., Furuya, S., Tasaka, A., Hamamura, K., & Ito, M. (2012). Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists. Bioorganic and Medicinal Chemistry, 20(1), 422-434. https://doi.org/10.1016/j.bmc.2011.10.067

Yamamoto, S, Matsunaga, N, Hitaka, T, Yamada, M, Hara, T, Miyazaki, J, Santou, T, Kusaka, M, Yamaoka, M, Kanzaki, N, Furuya, S, Tasaka, A, Hamamura, K & Ito, M 2012, 'Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists', Bioorganic and Medicinal Chemistry, vol. 20, no. 1, pp. 422-434. https://doi.org/10.1016/j.bmc.2011.10.067

@article{5e7e9075cfa8445dacc0cef3e16a944a,

title = "Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists",

abstract = "A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5- (hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3- carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.",

keywords = "1-Arylmethyl-4-phenylpyrrole derivatives, Androgen receptor antagonists, Castration-resistant prostate cancers",

author = "Satoshi Yamamoto and Nobuyuki Matsunaga and Takenori Hitaka and Masami Yamada and Takahito Hara and Junichi Miyazaki and Takashi Santou and Masami Kusaka and Masuo Yamaoka and Naoyuki Kanzaki and Shuichi Furuya and Akihiro Tasaka and Kazumasa Hamamura and Mitsuhiro Ito",

year = "2012",

month = jan,

day = "1",

doi = "10.1016/j.bmc.2011.10.067",

language = "English",

volume = "20",

pages = "422--434",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Limited",

number = "1",

}

TY - JOUR

T1 - Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists

AU - Yamamoto, Satoshi

AU - Matsunaga, Nobuyuki

AU - Hitaka, Takenori

AU - Yamada, Masami

AU - Hara, Takahito

AU - Miyazaki, Junichi

AU - Santou, Takashi

AU - Kusaka, Masami

AU - Yamaoka, Masuo

AU - Kanzaki, Naoyuki

AU - Furuya, Shuichi

AU - Tasaka, Akihiro

AU - Hamamura, Kazumasa

AU - Ito, Mitsuhiro

PY - 2012/1/1

Y1 - 2012/1/1

N2 - A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5- (hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3- carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.

AB - A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5- (hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3- carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.

KW - 1-Arylmethyl-4-phenylpyrrole derivatives

KW - Androgen receptor antagonists

KW - Castration-resistant prostate cancers

UR - http://www.scopus.com/inward/record.url?scp=84855191808&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84855191808&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2011.10.067

DO - 10.1016/j.bmc.2011.10.067

M3 - Article

C2 - 22094279

AN - SCOPUS:84855191808

SN - 0968-0896

VL - 20

SP - 422

EP - 434

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 1

ER -

Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this