Abstract
The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.
MeSH terms
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Alkylation
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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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Biomarkers / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cysteine / metabolism*
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Humans
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Lactones / chemical synthesis*
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Lactones / chemistry
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Lactones / pharmacology
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Naphthoquinones / chemical synthesis
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Naphthoquinones / chemistry
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Naphthoquinones / pharmacology
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Oncogene Protein v-akt / antagonists & inhibitors*
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Pyrans / chemical synthesis*
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Pyrans / chemistry
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Pyrans / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Biomarkers
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Lactones
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Naphthoquinones
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Pyrans
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frenolicin B
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medermycin
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kalafungin
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Oncogene Protein v-akt
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Cysteine