Geldanamycin inhibitors

Bedin M, Gaben AM, Saucier C, Mester J. (2004) Geldanamycin, an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest. Int J Cancer 109 643-652. 

Webb, C. P., C. D. Hose, S. Koochekpour, M. Jeffers, M. Oskarsson, E. Sausville, A. Monks, and G. F. Vande Woude. The geldanamycins are potent inhibitors of the hepatocyte growth factor/scatter factor-met-urokinase plasminogen activator-plasmin proteolytic network. Cancer Res. 60 342-9.2000. 

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]. 

The first signal transdnction modulator to enter clinical trials, other than a formal cyclin-dependent kinase or protein kinase C inhibitor, was the microbial prodnct 17-allylamino-geldanamycin (17-AAG, 36). This modnlator entered Phase I trials in 2001 and is currently in Phase II trials in a variety of cancers. Geldanamycin and its derivatives bind at the major ATP-binding site of the protein chaperone Hsp-90. The protein chaperones are emerging as attractive targets for cancer chemotherapy, and the reader is referred to three recent reviews for additional information (57-59). 

Several other molecules have recently been suggested as Hsp90 inhibitors, although their sites and specificity of action (if any) are far less well characterized than geldanamycin and radicicol. Coumarins, such as novobiocin, are known as inhibitors of bacterial type II DNA topo-isomerases such as DNA gyrase, binding to the ATP-binding site in... 

Fig. 9c. Hsp90 inhibitors, (c) Details from crystal structures of yeast Hsp90 N-terminal domain complexed with ADP (left), geldanamycin (middle), and radicicol (right). A detailed comparison of the binding of these compounds can be found in (Roe et al., 1999).

The total synthesis of the important Hsp90 inhibitor geldanamycin has been described. Two new aldol reactions, as general solutions to anti and syn 1,2 diol formation, were developed for this route. More efficient, convergent approaches, as alternatives to the linear route, were designed... 

Maytansine s ansa macrolide structure shows noteworthy similarities to those of the rifamycins [255], streptovaricins [256], tolypomycins [257], and geldanamycin [258]. The ansamycin antibiotics and their derivatives have aroused considerable interest as antiviral and antimicrobial agents, and as inhibitors of RNA tumor virus reverse transcriptases. 

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