Quinols as novel therapeutic agents. 2.1 4-(1-arylsulfonylindol- 2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and selective antitumor agents

Jane M. Berry, Tracey D. Bradshaw, Iduna Fichtner, Ruobo B. Ren, Carl H. Schwalbe, Goeffrey Wells, Eng-Hui Chew, Malcolm F.G. Stevens, Andrew D. Westwell

Research output: Contribution to journalArticle

Abstract

A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2, 5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound 1a and screened for antitumor activity. Synthesis of this novel series was accomplished via the "one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones1 with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol- 2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI50 value of 16 nM and a mean LC50 value of 2.24 μM in the NCI 60-cell-line screen, with LC50 activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol 1a exhibits two independent molecules, both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O, but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg.

Original languageEnglish
Pages (from-to)639-644
Number of pages6
JournalJournal of Medicinal Chemistry
Volume48
Issue number2
Early online date23 Dec 2004
DOIs
Publication statusPublished - 27 Jan 2005

Fingerprint

Hydroquinones
Antineoplastic Agents
Cells
Cell Line
Bearings (structural)
Lead compounds
Indoles
Tumor Cell Line
Heterografts
Colonic Neoplasms
Tumors
Hydrogen
Hydrogen bonds
Colon
Breast
Therapeutics
Crystal structure
Kidney
Atoms
Molecules

Keywords

  • animals
  • cell line
  • tumor
  • crystallography
  • x-ray
  • cyclohexanes
  • drug screening
  • humans
  • transplantations
  • heterologous

Cite this

Berry, Jane M. ; Bradshaw, Tracey D. ; Fichtner, Iduna ; Ren, Ruobo B. ; Schwalbe, Carl H. ; Wells, Goeffrey ; Chew, Eng-Hui ; Stevens, Malcolm F.G. ; Westwell, Andrew D. / Quinols as novel therapeutic agents. 2.1 4-(1-arylsulfonylindol- 2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and selective antitumor agents. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 2. pp. 639-644.
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Quinols as novel therapeutic agents. 2.1 4-(1-arylsulfonylindol- 2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and selective antitumor agents. / Berry, Jane M.; Bradshaw, Tracey D.; Fichtner, Iduna; Ren, Ruobo B.; Schwalbe, Carl H.; Wells, Goeffrey; Chew, Eng-Hui; Stevens, Malcolm F.G.; Westwell, Andrew D.

In: Journal of Medicinal Chemistry, Vol. 48, No. 2, 27.01.2005, p. 639-644.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Quinols as novel therapeutic agents. 2.1 4-(1-arylsulfonylindol- 2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and selective antitumor agents

AU - Berry, Jane M.

AU - Bradshaw, Tracey D.

AU - Fichtner, Iduna

AU - Ren, Ruobo B.

AU - Schwalbe, Carl H.

AU - Wells, Goeffrey

AU - Chew, Eng-Hui

AU - Stevens, Malcolm F.G.

AU - Westwell, Andrew D.

PY - 2005/1/27

Y1 - 2005/1/27

N2 - A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2, 5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound 1a and screened for antitumor activity. Synthesis of this novel series was accomplished via the "one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones1 with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol- 2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI50 value of 16 nM and a mean LC50 value of 2.24 μM in the NCI 60-cell-line screen, with LC50 activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol 1a exhibits two independent molecules, both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O, but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg.

AB - A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2, 5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound 1a and screened for antitumor activity. Synthesis of this novel series was accomplished via the "one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones1 with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol- 2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI50 value of 16 nM and a mean LC50 value of 2.24 μM in the NCI 60-cell-line screen, with LC50 activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol 1a exhibits two independent molecules, both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O, but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg.

KW - animals

KW - cell line

KW - tumor

KW - crystallography

KW - x-ray

KW - cyclohexanes

KW - drug screening

KW - humans

KW - transplantations

KW - heterologous

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U2 - 10.1021/jm040859h

DO - 10.1021/jm040859h

M3 - Article

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EP - 644

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 2

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