piperidines and monorden

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.

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Humans; Lactones; Macrolides; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1; Neoplasm Transplantation; Oncogene Protein pp60(v-src); Oximes; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-raf; Stereoisomerism; Structure-Activity Relationship; Transplantation, Heterologous; Tumor Cells, Cultured