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.
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.
Berry
Jane M
JM
Cancer Research UK Experimental Cancer Chemotherapy Research Group, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK.
Bradshaw
Tracey D
TD
Fichtner
Iduna
I
Ren
Ruobo
R
Schwalbe
Carl H
CH
Wells
Geoffrey
G
Chew
Eng-Hui
EH
Stevens
Malcolm F G
MF
Westwell
Andrew D
AD
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003512:Cyclohexanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous
C496960:4-(1-benzenesulfonyl-6-fluoro-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone; D000970:Antineoplastic Agents; D003510:Cyclohexanes; D003512:Cyclohexanones; D006873:Hydroquinones; D007211:Indoles; D013450:Sulfones