Radicicol

The first synthesis of radicicol was reported by Lampilas and Lett in 1992 [62] and served to confirm the absolute configuration of this molecule. The strategy 

H (4) NaHCOs, MeOH (5) SO2CI2, CH2CI2, O C 33% over five steps 

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Characterisation of the antibiotic monordene (also referred to as radicicol) with the elemental composition Cig/Zz/OgCl isolated from Monosporium bonorden gave the macrolide structure 1. The relative configuration of the H atoms on the two conjugated double bonds (6,7-cis, %,9-trans-) could be deduced from the 60 MHz H NMR spectrum The relative configuration of the C atoms 2-5, which encompass the oxirane ring as a partial structure, has yet to be established. 

Hsp90 is a molecular chaperon required for the refolding of proteins in cells exposed to environmental stress. It contains an ATP-binding pocket in its amino terminus. Several natural products, for example radicicol (230) (Scheme 48), bind to this pocket and inhibit its chaperon function, which is mirrored in enhanced proteosomal degradation of Hsp90 client proteins, so that compounds like 230 are of interest as novel anticancer agents. 

In a more recent and improved approach to cyclopropa-radicicol (228) [ 110], also outlined in Scheme 48, the synthesis was achieved via ynolide 231 which was transformed to the stable cobalt complex 232. RCM of 232 mediated by catalyst C led to cyclization product 233 as a 2 1 mixture of isomers in 57% yield. Oxidative removal of cobalt from this mixture followed by cycloaddition of the resulting cycloalkyne 234 with the cyclic diene 235 led to the benzofused macrolactone 236, which was converted to cyclopropa-radicicol (228). 

Scheme 48 Diene-ene RCM in Danishefsky s total synthesis of radicicol (230) [108] and its cycloprop a-analog 228 [109,110]...

Roe, S.M., Prodromou, C., O Brien, R., Ladbury, J.E., Piper, P.W. and Pearl, L.H. (1999) Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumour antibiotics radicicol and geldanamycin. Journal of Medicinal Chemistry, 42, 260-266. 

Fig. 1. Partial structure-activity relationships for radicicol (11) and monocillin (12).

Radicicol (11) isolated from C. chiversii was able to deplete cellular levels of the known Hsp90 client proteins ER and IGF-IR in MCF-7 human breast cancer cells. An IC50 value of 0.03 xM was obtained for the proliferation of MCF-7 cells treated with radicicol for three days. Currently, clinical trials are in progress with a less toxic CDA derivative, allylamino-17-demethoxygeldanamycin (17-AAC) (19). ... 

Mirrington RN, Ritchie E, Shoppee GW, Sternhell S, Taylor WG, Some metabolites oiNectria radicicola Gerlach Nilsson (Syn. Cylindrocarpon radicicolaSffr.) the structure of radicicol (monorden), Aust J Chem 19 1265—1284, 1966. 

Nozawa K, Nakajima S, Isolation of radicicol from Penicillium luteo-aurantium, and meleagrin, a new metabolite from Penicillium meleagrinum, J Nat Prod... 

Moulin E, Zoete V, Barluenga S, Karplus M, Winssinger N, Design, synthesis, and biological evaluation of HSP90 inhibitors based on conformational analysis of radicicol and its analogues, / Am Chem Soc 127 6999—7004, 2005. 

Soga, S., L. M. Neckers, T. W. Schulte, Y. Shiotsu, K. Akasaka, H. Narumi, T. Agatsuma, Y. Ikuina, C. Murakata, T. Tamaoki, and S. Akinaga. KF25706, a novel oxime derivative of radicicol, exhibits in vivo antitumor activity via selective depletion of Hsp90 binding signaling molecules. Cancer Res. 59 2931-8.1999. 

Initial attention in the development of Hsp90 inhibitors as anticancer agents was focused on two natural products, geldanamycin (compound 43, Fig. 8) and radicicol (also called monorden, compound 44, Fig. 8). These compounds bind into the ATP-binding cleft of the N-terminal domain of Hsp90 preventing the chaperone from cycling between its ADP and ATP-bound... 

As in the case of geldanamycin, synthetic efforts have been directed to identify radicicol derivatives with improved in vivo activity [188,189]. A representative example of this new class of inhibitors is KF58333 (compound 47, E-form isomer. Fig. 8), which increased the median survival time of mice inoculated with K562 chronic myelogenous leukemic cells when given i.v. at 50mg/kg [189]. 

In an approach to cyclopropa-radicicol also outlined in Scheme 64, the synthesis was achieved via ynolide... 

Roe SM, Prodromou C, O Brien R, Ladbury JE, Piper PW, Pearl LH (1999) Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin. J Med Chem 42 260... 

Tanaka Y, Kamei K, Otoguro K, Omura S (1999) Heme-Dependent Radical Generation Possible Involvement in Antimalarial Action of Non-Peroxide Microbial Metabolites, Nanaomycin A and Radicicol. J Antibiot 52 880... 

Radicicol-Type Macrolides a Promising Family of Anticancer Resorcylides... 

The tolerance of the RCM reaction to diverse functional groups is illustrated by the synthesis of 14-membered macrocycles monocillin I and radicicol, reported by Danishefsky and coworkers [63]. In the presence of catalyst G2, cyclization of dienic substrates 90 and 91, which comprise an allylic epoxide and a ketone function protected as a dithiane, occurs in 55-60% yields, generating intermediate macrocy-clic dienes 92 and 93 of 6E,ttZ stereochemistry (Scheme 2.36). It is interesting to... 

In order to optimize the antitumoral properties of radicicol, particularly in vivo, the same group synthesized the analogous cycloproparadicicol, where the epoxide function is replaced by a cyclopropane [64]. Submitted to the conditions of the previous RCM reaction (CH2C12, 42°C, 19h), cydopropyl triene 94 leads to the expected macrolide 95 in only 16% yield, along with 30% of the corresponding 28-membered dimeric macrocycle (Scheme 2.37). After numerous assays, the best conditions tested (toluene, 110 °C, 10 min) brought the yield up to 55%. In this case, the balance between thermodynamic and kinetic factors seems decisive for the course of the reaction. The fact that the monomeric product is predominant at elevated temperature indicates that this form is entropically favored. 

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