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.
Highlights
The phosphatidylinositol 3-kinase (PI3K) pathway controls cell proliferation, growth, differentiation, protein synthesis, glucose metabolism, migration, and apoptosis [1,2]
PIP3 levels are negatively regulated by phosphatase and tensin homologue (PTEN)
Once activated, signaling through Akt propagates to a diverse array of substrates, including the mammalian target of rapamycin, a key regulator of protein translation. mTOR is a serine/threonine protein kinase that interacts with several proteins, forming two distinct complexes named mTOR complex 1 and 2, Once activated, signaling through Akt propagates to a diverse array of substrates, including the mammalian target of rapamycin, a key regulator of protein translation. mTOR is a serine/threonine protein kinase that interacts with several pro2toefin25s, forming two distinct complexes named mTOR complex 1 and 2, which regulate different cellular processes including metabolism, growth, proliferation, wahnidchsurervgiuvlaalte[6d–i9f]f.erMenotrecoelvleurl,aracptrivoacteisosnesoifntchlue dpiantghwmaeytaibsonliostmv,egrrtoicwalt,ha,npdroiltifhearsatbioenen, asnhdowsunrvthivaatlm[6T–O9]R
Summary
The phosphatidylinositol 3-kinase (PI3K) pathway controls cell proliferation, growth, differentiation, protein synthesis, glucose metabolism, migration, and apoptosis [1,2]. Once activated, signaling through Akt propagates to a diverse array of substrates, including the mammalian target of rapamycin (mTOR), a key regulator of protein translation. MTOR is a serine/threonine protein kinase that interacts with several proteins, forming two distinct complexes named mTOR complex 1 (mTORC1) and 2 (mTORC2), Once activated, signaling through Akt propagates to a diverse array of substrates, including the mammalian target of rapamycin (mTOR), a key regulator of protein translation. Dual PI3K/mTOR inhibitors with pan class I PI3K and mTOR inhibition combine multiple therapeutic efficiencies in a single molecule They reduce the risk of drug resistance development and prevent PI3K/Akt reactivation due to the negative feedback loop. Tuhre asniddeccruhdaienalhdoemhyodloe gfuartnioisnheodf 6thwe oaxsimcaerr2i8edinomuotduesriantegyaieWldi.tTtihge/porxeisdeantcieveofcleavage p2r8ogcaevdeuurse tahnedopcpruodrteunailtdyethoybdueildfutrhneioshxaezdoltihcedoerxiivmateiv2e83i0n, wmhoicdhecroauteldybieeldco.nTshideerperdesence of 2a8s gaadvireecutsistohseteorpopf o21rt(uSnchiteymteo4b)u. ild the oxazolic derivative 30, which could be considered as a direct isoster of 21 (Scheme 4)
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