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.

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-ones(1) 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 GI(50) value of 16 nM and a mean LC(50) value of 2.24 muM in the NCI 60-cell-line screen, with LC(50) 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.

• Authors: Jane M Berry, Tracey D Bradshaw, Iduna Fichtner, Ruobo Ren, Carl H Schwalbe, Geoffrey Wells, Eng-Hui Chew, Malcolm F G Stevens, Andrew D Westwell
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 2 Pg. 639-44 (Jan 27 2005) ISSN: 0022-2623 [Print] United States
• PMID: 15658878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(1-benzenesulfonyl-6-fluoro-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone
• Antineoplastic Agents
• Cyclohexanes
• Cyclohexanones
• Hydroquinones
• Indoles
• Sulfones

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Crystallography, X-Ray
• Cyclohexanes (chemical synthesis, chemistry, pharmacology)
• Cyclohexanones (chemical synthesis, chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Female
• Humans
• Hydroquinones (chemical synthesis, chemistry, pharmacology)
• Indoles (chemical synthesis, chemistry, pharmacology)
• Mice
• Mice, Nude
• Structure-Activity Relationship
• Sulfones (chemical synthesis, chemistry, pharmacology)
• Transplantation, Heterologous