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 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.
Ikuina
Yoji
Y
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., 1188, Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. yoji.ikuina@kyowa.co.jp
Amishiro
Nobuyoshi
N
Miyata
Mayumi
M
Narumi
Hiroaki
H
Ogawa
Harumi
H
Akiyama
Tadakazu
T
Shiotsu
Yukimasa
Y
Akinaga
Shiro
S
Murakata
Chikara
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018942:Macrolides; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009368:Neoplasm Transplantation; D015688:Oncogene Protein pp60(v-src) / Q000037:antagonists & inhibitors; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007783:Lactones; D018942:Macrolides; D010091:Oximes; D010880:Piperidines; C475435:radicicol 6-(O-((piperidinocarbonyl)methyl)oxime); D015688:Oncogene Protein pp60(v-src); D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; C035359:monorden