Abstract
In this study, a series of novel 7 or 8-substituted 4-morpholine-quinazoline derivatives was designed and synthesized. Their PI3Kα inhibitory activities, antiproliferative activities against seven cancer cell lines, namely, PC-3, DU145, MCF-7, BT474, SK-BR-3, U937 and A431, were evaluated in vitro. Compound 17f proved to be a potential drug candidate with high PI3Kα inhibition activity (IC50 = 4.2 nM) and good antiproliferative activity. Compound 17f was also tested for its inhibitory activities against other kinases, such as PI3Kβ, PI3Kγ, PI3Kδ and mTOR, its effects on p-Akt (S473) and cell cycle. These results suggested that compound 17f could significantly inhibit the PI3K/Akt/mTOR pathway as a potent PI3K inhibitor and anticancer agent.
Keywords:
4-Morpholine-quinazolines; Antiproliferative effects; Kinase inhibitor; Phosphoinositide 3-kinase (PI3K).
Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Screening Assays, Antitumor
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Humans
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Molecular Structure
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Morpholines / chemical synthesis
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Morpholines / chemistry
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Morpholines / pharmacology*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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Quinolines / chemical synthesis
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Quinolines / chemistry
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Quinolines / pharmacology*
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Signal Transduction / drug effects
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Structure-Activity Relationship
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
Substances
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2-(2-aminopyrimidin-5-yl)-4-morpholino-N-(pyridin-3-yl)quinazolin-7-amine
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Antineoplastic Agents
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Quinolines
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases