Instituto de Química Médica (IQM, CSIC) , 28006 Madrid , Spain.
Centro de Química Orgánica "Lora-Tamayo" (CENQUIOR, CSIC) , 28006 Madrid , Spain.
J Med Chem. 2019 Apr 25;62(8):3958-3970. doi: 10.1021/acs.jmedchem.8b01988. Epub 2019 Apr 9.
We previously showed that a small molecule of natural origin, 1,2,3,4,6-penta- O-galloyl-β-d-glucopyranose (PGG), binds to capillary morphogenesis gene 2 (CMG2) with a submicromolar IC and also has antiangiogenic activity in vitro and in vivo. In this work, we synthetized derivatives of PGG with different sugar cores and phenolic substituents and tested these as angiogenesis inhibitors. In a high-throughput Förster resonant energy transfer-based binding assay, we found that one of our synthetic analogues (1,2,3,4,6-penta- O-galloyl-β-d-mannopyranose (PGM)), with mannose as central core and galloyl substituents, exhibit higher (up to 10×) affinity for CMG2 than the natural glucose prototype PGG and proved to be a potent angiogenesis inhibitor. These findings demonstrate that biochemical CMG2 binding in vitro predicts inhibition of endothelial cell migration ex vivo and antiangiogenic activity in vivo. The molecules herein described, and in particular PGM, might be useful prototypes for the development of novel agents for angiogenesis-dependent diseases, including blinding eye disease and cancer.
我们之前曾表明，一种天然来源的小分子 1,2,3,4,6-五-O-没食子酰基-β-d-葡萄糖（PGG）与毛细血管形态发生基因 2（CMG2）结合的 IC 为亚微摩尔级，并且在体外和体内均具有抗血管生成活性。在这项工作中，我们合成了具有不同糖核和酚取代基的 PGG 衍生物，并将其作为血管生成抑制剂进行了测试。在基于Förster 共振能量转移的高通量结合测定中，我们发现我们的一种合成类似物（1,2,3,4,6-五-O-没食子酰基-β-d-甘露吡喃糖（PGM）），以甘露糖为中心核和没食子酰取代基，对 CMG2 的亲和力比天然葡萄糖原型 PGG 高（高达 10 倍），并且被证明是一种有效的血管生成抑制剂。这些发现表明，体外的 CMG2 生化结合可预测内皮细胞迁移的体外抑制和体内抗血管生成活性。本文描述的分子，特别是 PGM，可能是开发新型血管生成依赖性疾病（包括致盲眼病和癌症）治疗药物的有用原型。
