Abstract
Our lead compound for a phosphoinositide 3-kinase (PI3K) inhibitor (1) was metabolically unstable because of rapid glucuronidation of the phenol moiety. Based on structure-activity relationship (SAR) information and a FlexSIS docking simulation score, aminopyrimidine was identified as a bioisostere of phenol. An X-ray structure study revealed a hydrogen bonding pattern of aminopyrimidine derivatives. Finally, aminopyrimidine derivatives 33 showed strong tumor growth inhibition against a KPL-4 breast cancer xenograft model in vivo.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Breast Neoplasms / drug therapy
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Cell Line, Tumor
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Crystallography, X-Ray
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Enzyme Activation / drug effects
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Female
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Glucuronic Acid / chemistry*
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Humans
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Hydrogen Bonding
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Inhibitory Concentration 50
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Mice
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Molecular Structure
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Phenols / chemistry*
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Phosphoinositide-3 Kinase Inhibitors*
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Phenols
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Phosphoinositide-3 Kinase Inhibitors
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Pyrimidines
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Pyrroles
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pyrrolopyrimidine
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Glucuronic Acid