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Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists.

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 ?,?-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.

SUBMITTER: Neochoritis CG 

PROVIDER: S-EPMC6404402 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists.

Neochoritis Constantinos G CG   Kazemi Miraki Maryam M   Abdelraheem Eman M M EMM   Surmiak Ewa E   Zarganes-Tzitzikas Tryfon T   Łabuzek Beata B   Holak Tad A TA   Dömling Alexander A  

Beilstein journal of organic chemistry 20190220

Macrocycles were designed to antagonize the protein-protein interaction p53-MDM2 based on the three-finger pharmacophore F<sup>19</sup>W<sup>23</sup>L<sup>25</sup>. 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  ...[more]

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