Design,Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2-d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors |
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Authors: | Fré dé ric Buron,Nuno Rodrigues,Thibault Saurat,Marie Aude Hiebel,Sté phane Bourg,Pascal Bonnet,Reine Nehmé ,Philippe Morin,Nathalie Percina,Justine Corret,Bé atrice Vallé e,Remy le Guevel,Marie-Lise Jourdan,Hé lè ne Bé né detti,Sylvain Routier |
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Abstract: | 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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Keywords: | pyridopyrimidine synthesis PI3K and mTOR kinase inhibition molecular modeling cell effects |
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