Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity

Ken ichi Morishita, Nobumasa Yakushiji, Fuminori Ohsawa, Kayo Takamatsu, Nobuyasu Matsuura, Makoto Makishima, Masatoshi Kawahata, Kentaro Yamaguchi, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthy l)amino]nicotinic acid (5a) is a moderately RXRα-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists.

Original languageEnglish
Pages (from-to)1001-1003
Number of pages3
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number3
DOIs
Publication statusPublished - Feb 1 2009

Fingerprint

Retinoid X Receptors
Sulfonamides
Switches
Ligands
Allergies
Niacin
Tamoxifen
Paclitaxel
Lung Neoplasms
Hypersensitivity
Breast Neoplasms

Keywords

  • Antagonists
  • Molecular design
  • Retinoid X receptor
  • RXR
  • Sulfonamide

ASJC Scopus subject areas

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

Cite this

Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity. / Morishita, Ken ichi; Yakushiji, Nobumasa; Ohsawa, Fuminori; Takamatsu, Kayo; Matsuura, Nobuyasu; Makishima, Makoto; Kawahata, Masatoshi; Yamaguchi, Kentaro; Tai, Akihiro; Sasaki, Kenji; Kakuta, Hiroki.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 19, No. 3, 01.02.2009, p. 1001-1003.

Research output: Contribution to journalArticle

Morishita, KI, Yakushiji, N, Ohsawa, F, Takamatsu, K, Matsuura, N, Makishima, M, Kawahata, M, Yamaguchi, K, Tai, A, Sasaki, K & Kakuta, H 2009, 'Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity', Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 3, pp. 1001-1003. https://doi.org/10.1016/j.bmcl.2008.11.086
Morishita, Ken ichi ; Yakushiji, Nobumasa ; Ohsawa, Fuminori ; Takamatsu, Kayo ; Matsuura, Nobuyasu ; Makishima, Makoto ; Kawahata, Masatoshi ; Yamaguchi, Kentaro ; Tai, Akihiro ; Sasaki, Kenji ; Kakuta, Hiroki. / Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity. In: Bioorganic and Medicinal Chemistry Letters. 2009 ; Vol. 19, No. 3. pp. 1001-1003.
@article{a7b62c9c950e40c39b34bae560ab31d8,
title = "Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity",
abstract = "Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthy l)amino]nicotinic acid (5a) is a moderately RXRα-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists.",
keywords = "Antagonists, Molecular design, Retinoid X receptor, RXR, Sulfonamide",
author = "Morishita, {Ken ichi} and Nobumasa Yakushiji and Fuminori Ohsawa and Kayo Takamatsu and Nobuyasu Matsuura and Makoto Makishima and Masatoshi Kawahata and Kentaro Yamaguchi and Akihiro Tai and Kenji Sasaki and Hiroki Kakuta",
year = "2009",
month = "2",
day = "1",
doi = "10.1016/j.bmcl.2008.11.086",
language = "English",
volume = "19",
pages = "1001--1003",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "3",

}

TY - JOUR

T1 - Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity

AU - Morishita, Ken ichi

AU - Yakushiji, Nobumasa

AU - Ohsawa, Fuminori

AU - Takamatsu, Kayo

AU - Matsuura, Nobuyasu

AU - Makishima, Makoto

AU - Kawahata, Masatoshi

AU - Yamaguchi, Kentaro

AU - Tai, Akihiro

AU - Sasaki, Kenji

AU - Kakuta, Hiroki

PY - 2009/2/1

Y1 - 2009/2/1

N2 - Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthy l)amino]nicotinic acid (5a) is a moderately RXRα-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists.

AB - Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthy l)amino]nicotinic acid (5a) is a moderately RXRα-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists.

KW - Antagonists

KW - Molecular design

KW - Retinoid X receptor

KW - RXR

KW - Sulfonamide

UR - http://www.scopus.com/inward/record.url?scp=58849150709&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58849150709&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2008.11.086

DO - 10.1016/j.bmcl.2008.11.086

M3 - Article

C2 - 19095448

AN - SCOPUS:58849150709

VL - 19

SP - 1001

EP - 1003

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 3

ER -