Structure-activity relationship of the inhibitory effects of flavonoids on nitric oxide production in RAW264.7 cells

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 2; pp. 779 - 788
• Main Authors: Jiang, Wen-Jun, Daikonya, Akihiro, Ohkawara, Mitsuyoshi, Nemoto, Takashi, Noritake, Ryusuke, Takamiya, Tomoko, Kitanaka, Susumu, Iijima, Hiroshi
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.01.2017; Elsevier
• Subjects: Animals; Biochemistry & Molecular Biology; Biological Products - chemistry; Biological Products - isolation & purification; Biological Products - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Comparative molecular field analysis; Dose-Response Relationship, Drug; Flavonoid; Flavonoids - chemistry; Flavonoids - isolation & purification; Flavonoids - pharmacology; Life Sciences & Biomedicine; Macrophage; Mice; Models, Molecular; Molecular Structure; Nitric oxide; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - biosynthesis; Pharmacology & Pharmacy; Physical Sciences; RAW 264.7 Cells; Rhodiola - chemistry; Science & Technology; Sophora - chemistry; Structure-Activity Relationship; NO; Comparative molecular field analysis; MBNGWHIJMBWFHU-UHFFFAOYSA-N; Flavonoid; AOLOMULCAJQEIG-UHFFFAOYSA-N; LPS; IFN-γ; ONKNGUOZRAKQPG-UHFFFAOYSA-N; Nitric oxide; Structure-activity relationship; DANYIYRPLHHOCZ-UHFFFAOYSA-N; FVFZGRNGSUVGKQ-UHFFFAOYSA-N; CoMFA; Macrophage; GEOMETRIES; MECHANISM; CYTOKINE; INFLAMMATION; SINAPIC ACID; MMFF94; BINDING; MOLECULAR-FORCE FIELD
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.11.055

[Display omitted] 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-γ. The isolated flavonoids carry symmetric substitutions in the B ring (R3′=R5′). 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 q2 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.