Document Detail


Synthesis of 2-arylindole derivatives and evaluation as nitric oxide synthase and NFκB inhibitors.
MedLine Citation:
PMID:  23044819     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Development of small molecule drug-like inhibitors blocking both nitric oxide synthase and NFκB could offer a synergistic therapeutic approach in the prevention and treatment of inflammation and cancer. During the course of evaluating the biological potential of a commercial compound library, 2-phenylindole (1) displayed inhibitory activity against nitrite production and NFκB with IC(50) values of 38.1 ± 1.8 and 25.4 ± 2.1 μM, respectively. Based on this lead, synthesis and systematic optimization have been undertaken in an effort to find novel and more potent nitric oxide synthase and NFκB inhibitors with antiinflammatory and cancer preventive potential. First, chemical derivatizations of 1 and 2-phenylindole-3-carboxaldehyde (4) were performed to generate a panel of N-alkylated indoles and 3-oxime derivatives 2–7. Second, a series of diversified 2-arylindole derivatives (10) were synthesized from an array of substituted 2-iodoanilines (8) and terminal alkynes (9) by applying a one-pot palladium catalyzed Sonogashira-type alkynylation and base-assisted cycloaddition. Subsequent biological evaluations revealed 3-carboxaldehyde oxime and cyano substituted 2-phenylindoles 5 and 7 exhibited the strongest nitrite inhibitory activities (IC(50) = 4.4 ± 0.5 and 4.8 ± 0.4 μM, respectively); as well as NFκB inhibition (IC(50) = 6.9 ± 0.8 and 8.5 ± 2.0 μM, respectively). In addition, the 6′-MeO-naphthalen-2′-yl indole derivative 10at displayed excellent inhibitory activity against NFκB with an IC(50) value of 0.6 ± 0.2 μM.
Authors:
Xufen Yu; Eun-Jung Park; Tamara P Kondratyuk; John M Pezzuto; Dianqing Sun
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Organic & biomolecular chemistry     Volume:  10     ISSN:  1477-0539     ISO Abbreviation:  Org. Biomol. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-26     Completed Date:  2013-03-22     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  101154995     Medline TA:  Org Biomol Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  8835-47     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents / chemical synthesis,  chemistry*,  pharmacology*
Cell Line
Cell Survival / drug effects
Humans
Indoles / chemical synthesis,  chemistry*,  pharmacology*
Inhibitory Concentration 50
NF-kappa B / antagonists & inhibitors*
Nitric Oxide Synthase / antagonists & inhibitors*
Grant Support
ID/Acronym/Agency:
5P20RR016467-11/RR/NCRR NIH HHS; 8P20GM103466-11/GM/NIGMS NIH HHS; P20 GM103466/GM/NIGMS NIH HHS; P20 RR016467/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Indoles; 0/NF-kappa B; EC 1.14.13.39/Nitric Oxide Synthase; MQD44HV3P1/2-phenylindole
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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