|
Ikuina Y, Amishiro N, Miyata M, Narumi H, Ogawa H, Akiyama T,
Shiotsu Y, Akinaga S, Murakata C.
Synthesis and antitumor activity of novel O-carbamoylmethyloxime
derivatives of radicicol.
J Med Chem. 2003 Jun 5;46(12):2534-41
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co.,
Ltd., 1188, Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka
411-8731, Japan. yoji.ikuina@kyowa.co.jp
Radicicol, 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.
PMID: 12773056
|
