| 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 |
Related Documents
:
|
11671449 - Absolute rate constants for iminyl radical reactions. 15292949 - Measurement of chemical oxygen demand (cod) in natural water samples by flow injection ... 23666479 - A new nad(h)-dependent meso-2,3-butanediol dehydrogenase from an industrially potential... 22283619 - Copper catalyzed petasis-type reaction: a general route to alpha-substituted amides fro... 21526779 - Synthesis and macrophage activation of lentinan-mimic branched amino polysaccharides: c... 19716429 - Engineering the pichia pastoris methanol oxidation pathway for improved nadh regenerati... 19785149 - Benzyl alcohol oxidation in supercritical carbon dioxide: spectroscopic insight into ph... 21562659 - Design and synthesis of nitrogen-containing calcined polymer/carbon nanotube hybrids th... 11671449 - Absolute rate constants for iminyl radical reactions. |
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: 2013-04-16 |
Medline Journal Info:
|
Nlm Unique ID: 101154995 Medline TA: Org Biomol Chem Country: England |
Other Details:
|
Languages: eng Pagination: 8835-47 Citation Subset: IM |
Affiliation:
|
Department of Pharmaceutical Sciences, College of Pharmacy, University of Hawai'i at Hilo, Hilo, HI, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| 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 |
| 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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Exon and intron definition in pre-mRNA splicing.
Next Document: Binary regression: Total gain in positive and negative predictive values.