Abstract
4-Morpholin-4-ylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine 2a was discovered in our chemical library as a novel p110alpha inhibitor with an IC(50) of 1.4 microM. By structural modification of 2a, the 2-aryl-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidine derivative 10e was discovered as a p110alpha inhibitor with approximately 400-fold greater potency than 2a. Evaluation of isoform selectivity showed that 10e is a potent inhibitor of p110beta. Furthermore, 10e showed anti-proliferative activity in various cell lines, including multi-drug resistant MCF7/ADR-res cells, and was effective against HeLa human cervical tumor xenografts in nude mice.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Chemistry, Pharmaceutical / methods
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Class I Phosphatidylinositol 3-Kinases
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Drug Design
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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HeLa Cells
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Humans
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Inhibitory Concentration 50
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Mice
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Molecular Conformation
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Neoplasm Transplantation
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Phosphoinositide-3 Kinase Inhibitors*
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Pyridines / chemical synthesis*
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Pyrimidines / chemical synthesis*
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Phosphoinositide-3 Kinase Inhibitors
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Pyridines
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Pyrimidines
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Class I Phosphatidylinositol 3-Kinases
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PIK3CB protein, human