Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 25, Issue 2, Pages 779-788Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.11.055
Keywords
Flavonoid; Nitric oxide; Macrophage; Structure-activity relationship; Comparative molecular field analysis
Funding
- Academic Frontier Project of the Ministry of Education, Culture, Sports, Science, and Technology, Japan
- Otsuka Toshimi Scholarship Foundation
- Watanuki International Scholarship Foundation
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We isolated flavonoids from herbal specimens from the Tibetan region (Sophora yunnanensis and Rhodiola sacra) that suppress nitric oxide (NO) production in macrophages stimulated by lipopolysaccharide and interferon-gamma. The isolated flavonoids carry symmetric substitutions in the B ring (R-3' = R-5'). We analyzed the quantitative structure-activity relationship of the inhibitory activity by comparative molecular field analysis (CoMFA) using this series of flavonoids. Use of flavonoids with symmetrical substitutions in the B ring made it simpler to align molecules because it was not necessary to consider a huge number of combinations due to the B-ring conformation. The CoMFA model, whose cross-validated q(2) value was 0.705, suggested the existence of a hydroxy group at the 5-position, the choice of the A/C-ring scaffold (chromane or chromene) and electrostatic field around the B ring are important for NO inhibitory activity. Flavonoids synthesized based on the CoMFA model exhibited significant inhibitory potential against NO production, validating the predictive capability of the CoMFA model. (C) 2016 Elsevier Ltd. All rights reserved.
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