College of Pharmacy, Kangwon National University, Chunchon 200-701, Korea.
Arch Pharm Res. 2009 Nov;32(11):1525-31. doi: 10.1007/s12272-009-2104-2.
Previously, a synthetic biflavone having a C-C (6-6") linkage ([6,6"]biflavone, BF6-6) was shown to possess considerable anti-inflammatory activity. The present investigation was conducted to develop more active anti-inflammatory biflavonoids having unique mechanisms of action based on the BF6-6 molecule. For this purpose, 5,7-dihydroxy[6,6"]biflavone (G168) was synthesized using Suzuki-Miyaura C-C cross coupling reaction. The anti-inflammatory activities of G168 were then examined on lipopolysaccharide-treated RAW 264.7 cells, carrageenan-induced paw edema and acetic acid-induced writhing in mice. It was found that G168 showed much stronger inhibition against cyclooxygenase-2-mediated PGE2 production than the original molecule, BF6-6. It also demonstrated inhibitory activity against inducible nitric oxide synthase (iNOS)-mediated NO production at least partly by the down-regulation of iNOS. Furthermore, G168, administered intraperitoneally at a dosage of 1-5 mg/kg, showed a potent in vivo anti-inflammatory activity on carrageenan-induced paw edema and analgesic activity on acetic acid-induced writhing in mice. Therefore, the newly synthesized biflavonoid, G168, may be used as a synthetic lead for new anti-inflammatory drug development.
先前，一种具有 C-C（6-6"）键的合成双黄酮（[6,6"]双黄酮，BF6-6）被证明具有相当强的抗炎活性。本研究旨在基于 BF6-6 分子开发具有独特作用机制的更有效的抗炎双黄酮。为此，使用 Suzuki-Miyaura C-C 交叉偶联反应合成了 5,7-二羟基[6,6"]双黄酮（G168）。然后在脂多糖处理的 RAW 264.7 细胞、角叉菜胶诱导的爪肿胀和醋酸诱导的扭体实验中检测了 G168 的抗炎活性。结果发现，G168 对环加氧酶-2 介导的 PGE2 产生的抑制作用比原始分子 BF6-6 强得多。它还通过下调 iNOS 至少部分抑制诱导型一氧化氮合酶（iNOS）介导的 NO 产生。此外，G168 以 1-5mg/kg 的剂量腹腔给药，在角叉菜胶诱导的爪肿胀和醋酸诱导的扭体实验中表现出很强的体内抗炎活性和镇痛活性。因此，新合成的双黄酮 G168 可用作新型抗炎药物开发的合成先导物。
