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

• Published in: Journal of medicinal chemistry Vol. 46; no. 12; pp. 2534 - 2541
• Main Authors: Ikuina, Yoji, Amishiro, Nobuyoshi, Miyata, Mayumi, Narumi, Hiroaki, Ogawa, Harumi, Akiyama, Tadakazu, Shiotsu, Yukimasa, Akinaga, Shiro, Murakata, Chikara
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 05-06-2003
• 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; Antineoplastic agent; Cell proliferation; Intravenous administration; Rat; Halophenols; V-Onc gene; Oxime; Oxygen heterocycle; Kidney; Signal transduction; Structure activity relation; Chlorine Organic compounds; Heat shock protein; Aromatic compound; Inhibition; Chemical synthesis; Human; Squamous cell carcinoma; Enzyme; Transferases; Rodentia; Enzyme inhibitor; Lactone; Malignant tumor; Tricyclic compound; In vitro; Mammary gland diseases; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Cell line; Treatment; Mouse; Kinase; Animal; Phenols; Carboxamide
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030110r

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.