Abstract
Radicicol (1), a macrocyclic antifungal antibiotic, is the lead compound of a novel class of heat shock protein 90 (Hsp90) inhibitors that result in the inhibition or degradation of Hsp90-associated proteins, such as v-src and Raf-1 kinases. New O-carbamoylmethyloxime derivatives of 1 were synthesized and evaluated for their in vitro antiproliferative activities against v-src- and K-ras-transformed cells and for their inhibitory activity against v-src tyrosine kinase. O-(Piperidinocarbonyl)methyloxime 9b, one of the most potent of these derivatives, exhibited more potent antiproliferative activity than 1 and its hydroxime KF25706 (2) and had an IC(50) of 25 nM for the inhibition of v-src kinase activity. Compound 9b was also found to decrease the Raf-1 protein level of KNRK5.2 cells. Furthermore, compound 9b exhibited significant antitumor activity when tested against MX-1 and A431 xenografts in nude mice.
MeSH terms
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Animals
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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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Drug Screening Assays, Antitumor
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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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Macrolides
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinase 1 / metabolism
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Neoplasm Transplantation
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Oncogene Protein pp60(v-src) / antagonists & inhibitors
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Oximes / chemical synthesis*
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Oximes / chemistry
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Oximes / pharmacology
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Phosphorylation
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Proto-Oncogene Proteins c-raf / metabolism
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Stereoisomerism
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Structure-Activity Relationship
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Transplantation, Heterologous
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Lactones
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Macrolides
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Oximes
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Piperidines
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radicicol 6-(O-((piperidinocarbonyl)methyl)oxime)
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Oncogene Protein pp60(v-src)
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Proto-Oncogene Proteins c-raf
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Mitogen-Activated Protein Kinase 1
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monorden