Synthesis and Antitumor Activity of Novel O-Carbamoylmethyloxime Derivatives of Radicicol

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 synthesiz...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2003-06, Vol.46 (12), p.2534-2541
Main Authors: Ikuina, Yoji, Amishiro, Nobuyoshi, Miyata, Mayumi, Narumi, Hiroaki, Ogawa, Harumi, Akiyama, Tadakazu, Shiotsu, Yukimasa, Akinaga, Shiro, Murakata, Chikara
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Chemotherapy
Drug Screening Assays, Antitumor
Humans
Lactones - chemical synthesis
Lactones - chemistry
Lactones - pharmacology
Macrolides
Medical sciences
Mice
Mice, Nude
Mitogen-Activated Protein Kinase 1 - metabolism
Neoplasm Transplantation
Oncogene Protein pp60(v-src) - antagonists & inhibitors
Oximes - chemical synthesis
Oximes - chemistry
Oximes - pharmacology
Pharmacology. Drug treatments
Phosphorylation
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Proto-Oncogene Proteins c-raf - metabolism
Stereoisomerism
Structure-Activity Relationship
Transplantation, Heterologous
Tumor Cells, Cultured
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Summary: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 IC50 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm030110r