Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
J Med Chem. 2012 Sep 27;55(18):8021-7. doi: 10.1021/jm3008695. Epub 2012 Sep 14.
Natural-product-derived bengamides possess potent antiproliferative activity and target human methionine aminopeptidases (MetAPs) for their cellular effects. Several derivatives were designed, synthesized, and evaluated as MetAP inhibitors. Here, we present four new X-ray structures of human MetAP1 in complex with the inhibitors. Together with the previous structures of bengamide derivatives with human MetAP2 and tubercular MtMetAP1c, analysis of the interactions of these inhibitors at the active site provides structural basis for further modification of these bengamide inhibitors for improved potency and selectivity as anticancer and antibacterial therapeutics.
天然产物衍生的苯甲酰胺具有很强的抗增殖活性，其细胞作用的靶标是人类蛋氨酸氨肽酶（MetAPs）。设计、合成了几种衍生物，并将其作为 MetAP 抑制剂进行了评估。在这里，我们呈现了与抑制剂结合的人 MetAP1 的四个新的 X 射线结构。结合先前与人类 MetAP2 和结核 MtMetAP1c 的苯甲酰胺衍生物的结构，对这些抑制剂在活性部位相互作用的分析为进一步修饰这些苯甲酰胺抑制剂提供了结构基础，以提高其作为抗癌和抗菌治疗剂的效力和选择性。
