Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: A comparison with tyrosine kinase and protein kinase C inhibition
Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: A comparison with tyrosine kinase and protein kinase C inhibition
复制标题
DOI：
10.1016/s0006-2952(97)82453-7
复制
发表时间：
1997-06-01
影响因子：
5.8
通讯作者：
Payrastre, B
中科院分区：
文献类型：
--
作者：
Agullo, G;GametPayrastre, L;Payrastre, B
根据其结构，类黄酮在体外对某些恶性细胞的生长和增殖显示出或多或少的有效抑制作用，并且这些作用被认为是由于抑制各种酶。我们研究了14种不同化学类别的黄酮类化合物对磷脂酰肌醇3-激酶α（PI 3-激酶α）活性的抑制作用，这种酶最近被证明在信号转导和细胞转化中起重要作用。十四类黄酮测试，杨梅是最有效的PI 3-激酶抑制剂（IC 50 = 1.8 μ M），而木犀草素和芹菜素也是有效的抑制剂，与IC 50值分别为8和12 μ M。非瑟酮和槲皮素，如以前报道的，也被发现显着抑制PI 3-激酶活性。还分析了相同的黄酮类化合物对表皮生长因子受体（EGF-R）、内源性酪氨酸激酶和牛脑蛋白激酶C（PKC）的抑制作用。在升高的剂量下，发现这些黄酮类化合物中的一些也引起EGF-R的PKC和酪氨酸激酶活性的显著抑制。构效关系研究表明，B环上羟基的位置、数目、取代度以及C2-C3键的饱和度是影响黄酮类化合物抑制PI 3-激酶活性的重要因素。它们也可能在抑制特异性方面发挥重要作用，并可能有助于为进一步设计这种脂质激酶的特异性抑制剂提供基础。最后，这些黄酮类化合物的抗肿瘤特性和它们的生物活性之间的可能关系进行了讨论。生物化学制药53;11：1649-1657，1997年。(C)1997年爱思唯尔科学公司
Depending on their structure, flavonoids display more or less potent inhibitory effects on the growth and proliferation of certain malignant cells in vitro, and these effects are thought re, be due to inhibition of various enzymes. We investigated the inhibitory action of fourteen flavonoids of different chemical classes on phosphatidylinositol 3-kinase alpha (PI 3-kinase alpha) activity, an enzyme recently shown to play an important role in signal transduction and cell transformation. Of the fourteen flavonoids tested, myricetin was the most potent PI 3-kinase inhibitor (IC50 = 1.8 mu M), while luteolin and apigenin were also effective inhibitors, with IC50 values of 8 and 12 mu M, respectively. Fisetin and quercetin, as previously reported, were also found to significantly inhibit PI 3-kinase activity. The same flavonoids were also analyzed for inhibition of epidermal growth factor receptor (EGF-R), intrinsic tyrosine kinase and bovine brain protein kinase C (PKC). At elevated doses, some of these flavonoids were found to also cause significant inhibition of PKC and tyrosine kinase activity of EGF-R. A structure-activity study indicated that the position, number and substitution of the hydroxyl group of the B ring, and saturation of the C2-C3 bond are important factors affecting flavonoid inhibition of PI 3-kinase. They may also play a significant role in specificity of inhibition and could help to provide a basis for the further design of specific inhibitors of this lipid kinase. Finally, possible relationships between the antitumoral properties of these flavonoids and their biological activities are discussed. BIOCHEM PHARMACOL 53;11:1649-1657, 1997. (C) 1997 Elsevier Science Inc.