氧杂蒽酮是自然界中最基本的植物化学物质之一。氧杂蒽酮及其衍生物的抗癌活性已被广泛研究。最近，我们发现从山竹（Garcinia mangostanal.）中分离出的一种有效的抗癌植物化学物质藤黄酮E（GE）在体外和体内表现出良好的抗癌作用。然而，人们对其对表皮生长因子受体 (EGFR) 和血管内皮生长因子受体 2 (VEGFR2) 活性的影响知之甚少。本研究旨在通过结构-活性关系分析从山竹衍生的氧杂蒽酮中鉴定有效的 EGFR 和 VEGFR2 双重抑制剂使用分子对接实验分析了氧杂蒽酮与 EGFR 和 VEGFR2 的相互作用。使用生物发光测定法测定 EGFR 和 VEGFR2 的激酶活性。大鼠主动脉环和基质胶塞血管生成测定用于评估离体和体内血管形成。建立乳腺肿瘤裸鼠模型，考察不同氧杂蒽酮的抗肿瘤作用。分子对接分析显示，GE与EGFR和VEGFR2紧密结合，结合能分别为-9.73和-9.56 kcal/mol。激酶活性评估表明，GE 强烈抑制 EGFR 和 VEGFR2 激酶活性，IC50 值分别为 315.4 和 158.2 nM。此外，GE 分别显着消除了 EGF 和 VEGF 诱导的 EGFR 和 VEGFR2 磷酸化。 GE还对癌细胞生长、内皮细胞迁移、侵袭和管形成表现出强大的抑制作用。离体和体内血管生成测定表明，GE 剂量依赖性地抑制大鼠主动脉、基质胶塞和转基因斑马鱼胚胎中的血管形成，最低有效浓度为 0.25 μM。此外，GE (2 mg/kg) 强烈抑制 MDA-MB-231 乳腺肿瘤异种移植小鼠的肿瘤生长并降低肿瘤重量。 GE 显着降低肿瘤组织中的微血管密度并下调 VEGFR2、EGFR 和 Ki67 的表达。本研究表明，GE 是所有测试的氧杂蒽酮中最有效的 EGFR 和 VEGFR2 双重抑制剂。这些发现可能为未来开发新型有效的 EGFR 和 VEGFR2 双重抑制剂提供有价值的信息。版权所有 © 2023。由 Elsevier GmbH 出版。

Xanthones are among the most fundamental phytochemicals in nature. The anti-cancer activities of xanthones and their derivatives have been extensively studied. Recently, we found that garcinone E (GE), an effective anti-cancer phytochemical isolated from mangosteen (Garcinia mangostanal.), showed promising anti-cancer effects in vitro and in vivo. However, little is known about its effects on epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) activity.This study aimed to identify potent dual EGFR and VEGFR2 inhibitors from mangosteen-derived xanthones using structure-activity relationship analyses.The interaction of xanthones with EGFR and VEGFR2 was analyzed using molecular docking experiments. The kinase activities of EGFR and VEGFR2 were determined using bioluminescence assays. The rat aortic ring and Matrigel plug angiogenesis assays were used to evaluate blood vessel formation ex vivo and in vivo. A breast tumor-bearing nude mouse model was established to examine the anti-tumor effects of different xanthones.Molecular docking analysis showed that GE bound tightly to EGFR and VEGFR2, with binding energies of -9.73 and -9.56 kcal/mol, respectively. Kinase activity assessment showed that GE strongly inhibited both EGFR and VEGFR2 kinase activity, with IC50 values of 315.4 and 158.2 nM, respectively. Moreover, GE significantly abolished the EGF- and VEGF-induced phosphorylation of EGFR and VEGFR2, respectively. GE also showed strong inhibitory effects on cancer cell growth, endothelial cell migration, invasion, and tube formation. Ex vivo and in vivo angiogenesis assays showed that GE dose-dependently suppressed blood vessel formation in the rat aorta, Matrigel plugs, and transgenic zebrafish embryos, with the lowest effective concentration of 0.25 μM. Furthermore, GE (2 mg/kg) strongly inhibited tumor growth and reduced tumor weight in MDA-MB-231 breast tumor-xenografted mice. GE significantly reduced microvessel density and downregulated the expression of VEGFR2, EGFR, and Ki67 in tumor tissues.The present study demonstrated that GE was the most potent dual inhibitor of EGFR and VEGFR2 among all xanthones tested. These findings may provide valuable information for the future development of novel and effective dual inhibitors of EGFR and VEGFR2.Copyright © 2023. Published by Elsevier GmbH.