Abstract
In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCdelta, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCalpha or delta isozymes.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects*
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Apoptosis / physiology
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Dose-Response Relationship, Drug
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Drug Design
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Enzyme Activators / chemical synthesis*
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Enzyme Activators / pharmacology
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Humans
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Isoenzymes / drug effects*
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Male
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Prostate / metabolism
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / physiopathology*
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Protein Kinase C / drug effects*
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Protein Kinase C / genetics
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Protein Kinase C / metabolism
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Protein Kinase C-alpha
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Protein Kinase C-delta
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Pyrrolidinones / chemical synthesis*
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Pyrrolidinones / pharmacology
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Stereoisomerism
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Enzyme Activators
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Isoenzymes
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Pyrrolidinones
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pyrollidone 15
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pyrollidone 2
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PRKCA protein, human
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PRKCD protein, human
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Protein Kinase C
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Protein Kinase C-alpha
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Protein Kinase C-delta