Design, Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2-d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Molecules Année : 2021

Design, Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2-d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors

Pascal Bonnet
Reine Nehmé
Philippe Morin
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Béatrice Vallée
Hélène Bénédetti

Résumé

This work describes the synthesis, enzymatic activities on PI3K and mTOR, in silico docking and cellular activities of various uncommon 2,4,7 trisubstituted pyrido[3,2-d]pyrimidines. The series synthesized offers a chemical diversity in C-7 whereas C-2 (3-hydroxyphenyl) and C-4 groups (morpholine) remain unchanged, in order to provide a better understanding of the molecular determinants of PI3K selectivity or dual activity on PI3K and mTOR. Some C-7 substituents were shown to improve the efficiency on kinases compared to the 2,4-di-substituted pyrimidopyrimidine derivatives used as references. Six novel derivatives possess IC50 values on PI3Kα between 3 and 10 nM. The compounds with the best efficiencies on PI3K and mTOR induced micromolar cytotoxicity on cancer cell lines possessing an overactivated PI3K pathway.
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Dates et versions

hal-03348966 , version 1 (25-10-2021)

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Frédéric Buron, Nuno Rodrigues, Thibault Saurat, Marie-Aude Hiebel, Stéphane Bourg, et al.. Design, Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2-d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors. Molecules, 2021, 26 (17), pp.5349. ⟨10.3390/molecules26175349⟩. ⟨hal-03348966⟩
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