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

Abstract

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.

Insights into Radicicol Biosynthesis via Heterologous Synthesis of Intermediates and Analogs

“…Pochonin D (11), which is the chlorinated version of 6, appears to be biosynthetically accessible through the action of the FAD-dependent halogenase Rdc2 (Fig. 1B, box IV).…”

“…This is a unique structural feature of radicicol compared with other RALs, which has been explored as a reactive handle for oxime formation (11,14). Two possible pathways leading to the instal- lation of the C2Ј ketone of radicicol have been proposed (Fig.…”

Divergent Synthesis of a Pochonin Library Targeting HSP90 and In Vivo Efficacy of an Identified Inhibitor

“…[21] Akinaga and co-workers overcame this limitation by converting radicicol into an oxime, which showed significant antitumor activity (reduction in tumor growth) in animal models. [21][22][23] Mindful of the labile epoxide, Danishefsky and co-workers reported a cyclopropyl analogue of radicicol which was nearly as effective in cellular assays; however, its efficacy in animals has not been reported. [24,25] More recently, Moody and co-workers reported the synthesis of radicicolrelated resorcylides, and explored the importance of the size of the macrocyle.…”

“…[31] Similar discrepancies between HSP90 affinity measured by a fluorescence polarization assay and ATPase inhibition have been noted for inhibitors based on the resorcylides motif. [26] Based on the observation that oxime substitutions in the pochonin series did not affect the HSP90 activity, and inspired by previous success with radicicol, [21][22][23] we developed a divergent synthesis that provided rapid access to this class of compounds. Readily available intermediate 6 was deprotonated with LDA (Scheme 2) and treated with Weinreb Angewandte Chemie amide 7.…”

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

“…43 The O-carbamoylmethyloxime derivative of radicicol, KF25706, inhibits v-Src-and k-Ras-activated signaling. 44,45 Macbecin 46 and its non-quinone compound that target Hsp90 have been reported, 47 indicating that the quinone moiety of macbecin is not a prerequisite for Hsp90 inhibition. The non-quinone derivative of macbecin has significantly improved the binding affinity to Hsp90 in vitro.…”