Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists (Beilstein Journal of Organic Chemistry)

Abstract Macrocycles were designed to antagonize the protein–protein interaction p53-MDM2 based on the three-finger pharmacophore F19W23L25. The synthesis was accomplished by a rapid, one-pot synthesis of indole-based macrocycles based on Ugi macrocyclization. The reaction of 12 different α,ω-amino acids and different indole-3-carboxaldehyde derivatives afforded a unique library of macrocycles otherwise difficult to access. Screening of the library for p53-MDM2 inhibition by fluorescence polarization and 1H,15N HSQC NMR measurements confirm MDM2 binding. Beilstein J. Org. Chem. 2019, 15, 513–520. doi:10.3762/bjoc.15.45