Estrada-Ortiz Natalia, Neochoritis Constantinos G, Twarda-Clapa Aleksandra, Musielak Bogdan, Holak Tad A, Dömling Alexander
Department of Drug Design, University of Groningen, A. Deusinglaan 1, Groningen 9700AV, The Netherlands.
Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
ACS Med Chem Lett. 2017 Sep 20;8(10):1025-1030. doi: 10.1021/acsmedchemlett.7b00219. eCollection 2017 Oct 12.
Based on a combination of an Ugi four component reaction and a ring closing metathesis, a library of novel artificial macrocyclic inhibitors of the p53-MDM2 interaction was designed and synthesized. These macrocycles, alternatively to stapled peptides, target for the first time the large hydrophobic surface area formed by Tyr67, Gln72, His73, Val93, and Lys94 yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using fluorescence polarization (FP) assay and H-N two-dimensional HSQC nuclear magnetic resonance experiments.
基于乌吉四组分反应和闭环复分解反应的组合，设计并合成了一个新型的p53-MDM2相互作用人工大环抑制剂文库。这些大环化合物首次靶向由Tyr67、Gln72、His73、Val93和Lys94形成的大疏水表面积，替代了固定肽，产生了纳摩尔范围内对MDM2有亲和力的衍生物。使用荧光偏振（FP）测定法和H-N二维HSQC核磁共振实验评估了它们与MDM2的结合亲和力。
