Geldanamycin Derivatives

Maroney, A.C. et al. 2006. Dihydroquinone ansamycins toward resolving the conflict between low in vitro affinity and high cellular potency of geldanamycin derivatives. Biochemistry 45, 5678-5685. McLaughlin, S.H., H.W. Smith, and S.E. Jackson. 2002. Stimulation of the weak ATPase activity of human hsp90 by a client protein. J. Mol. Biol. 315, 787-798. 

Allylamino,17-demethoxygeldanamycin (3), a geldanamycin derivative, is now in clinical fiial. 

Kasuya Y, Lu Z-R, Kopeckova P, Tabibi SE, Kopecek J. Influence of the structure of drug moieties on the in vitro efficacy of HPMA copolymer-geldanamycin derivative conjugates. Pharm Res 2002 19(2) 115-123. 

Nishiyama N, Nori A, Malugin A, Kasuya Y, Kopeckova P, Kopecek J. Free and N-(2-hydroxypropyl)methacrylamide copolymer-bound geldanamycin derivative induce different stress responses in A2780 human ovarian carcinoma cells. Cancer Res 2003 63(22) 7876-7882. 

A geldanamycin-derived inhibitor has entered phase II clinical trials and initial results are promising, providing proof of principle for Hsp90 inhibitors as cancer therapeutics. Pyrazole-type compounds such as A show some of the chemotypes recently identified as potent inhibitors of Hsp90. We now report the synthesis of two pyrazole-type compounds B, and C as potential inhibitors of Hsp90. The synthesis of compound B has been completed, and C is in progress. 

In view of the previously outlined adverse properties associated with 17-AAG, the more water-soluble and significantly less toxic geldanamycin derivative 17-desmetho)y-dimethylaminoethylaminogeldanamycin, 3 (17-DMAG ... 

Infinity Pharmaceuticals also reported the highly soluble geldanamycin-derived 17-amino-17-desmetho5tygeldanamycin 5 (17-AG also known as... 

The 19-substituted geldanamycin derivatives were also treated with amines to obtain the corresponding 17-AAG and 17-DMAG analogues. These were analysed in several cellular systems to test their toxicity in comparison to geldanamycin, 17-AAG and 17-DMAG. The data shown in Table 2.1 compare the toxicity profiles of the compounds against human umbilical... 

Several geldanamycin derivatives have shown low in vitro antimicrobial activities, while the substituted phenazines related to geldanazine gave minimal inhibition of E. coli RNA polymerase. Although geldanamycin itself, with no substituents at C-18 or C-19, did not inhibit MSV RNA-dependent DNA polymerase, a number of phenoxazinone and phenazine derivatives of geldanamycin (Fig. 24) inhibit RLV reverse transcriptase, as noted above. 

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