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Biotin-GA - Labeled GA Analogue
Biotin-GA was generated by biotinylation of geldanamycin at the C17 position. This labeled
GA can be used to identify novel Hsp90 inhibitors through time-resolved fluorescence
resonance energy transfer-based HTS that measures the binding of biotin-GA to the Nterminal
ATP-binding domain of Hsp90 10 .
17-AAGH2 & 17-DMAGH2 - Hydroquinone GA Analogues
The selective toxicity of benzoquinone ansamycins in tumor cells can be explained by
their reduction to hydroquinones. Indeed, many human cancer cells express at high
levels NAD(P)H:quinone oxidoreductase 1 (NQO1), a flavoenzyme that catalyzes the
direct reduction of quinones to hydroquinones. NQO1 has been shown to reduce
17-AAG and to increase the sensitivity to 17-AAG of cancer cell lines 11 . Recent studies
have demonstrated that the reduction product of 17-AAG, 17AAGH2, is a more
potent inhibitor of Hsp90 than the 17-AAG itself 12 , as well as 17-DMAGH2 compared
to 17-DMAG 13 .
InvivoGen provides 17-AAGH2 and 17-DMAGH2 produced by reduction of 17-AAG
and 17-DMAG respectively using a chemical reducing agent. Their purity is 99%.
www.invivogen.com/inhibitors
Biotin-GA
C56H88N8O12S
MW: 1097
Purity: 99%
1. Whitesell L. et al., 1994. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic
transformation. PNAS 91(18):8324-8. 2. Neckers L., 2002. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 8(4 Suppl):S55-61. 3. Schulte TW. & Neckers LM., 1998.
The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol 42(4):273-9.
4. Agnew EB. et al. 2001. Measurement of the novel antitumor agent 17-(allylamino)-17-demethoxygeldanamycin in human plasma by high-performance liquid chromatography. J Chromatogr B
Biomed Sci Appl 755:237-43. 5. Workman P., 2003. Overview: translating Hsp90 biology into Hsp90 drugs. Curr Cancer Drug Targets 3(5):297-300. 6. Egorin MJ, et al., 2002. Pharmacokinetics,
tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats. Cancer Chemother Pharmacol 49(1):7-
19. 7. Tian ZQ. et al., 2004. Synthesis and biological activities of novel 17-aminogeldanamycin derivatives.Bioorg Med Chem. 12(20):5317-29. 8. Mandler R. et al., 2004. Herceptin-geldanamycin
immunoconjugates: pharmacokinetics, biodistribution, and enhanced antitumor activity. Cancer Res. 64(4):1460-7. 9. Mandler R. et al., 2002. Modifications in synthesis strategy improve the
yield and efficacy of geldanamycin-herceptin immunoconjugates. Bioconjug Chem. 13(4):786-91. 10. Zhou V. et al., 2004. A time-resolved fluorescence resonance energy transfer-based HTS
assay and a surface plasmon resonance-based binding assay for heat shock protein 90 inhibitors. Anal Biochem. 331(2):349-57. 11. Kelland LR et al., 1999. DT-Diaphorase expression and
tumor cell sensitivity to17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J Natl Cancer Inst. 91(22):1940-9. 12. Guo W et al., 2005. Formation of 17-allylaminodemethoxygeldanamycin
(17-AAG) hydroquinone by NAD(P)H:quinone oxidoreductase 1: role of 17-AAG hydroquinone in heat shock protein 90 inhibition. Cancer Res. 65(21):10006-15. 13.
Guo W et al., 2006. The bioreduction of a series of benzoquinone ansamycins by NAD(P)H:quinone oxidoreductase 1 to more potent heat shock protein 90 inhibitors, the hydroquinone
ansamycins. Mol Pharmacol. 70(4):1194-203.
DNA Synthesis Inhibitors
5-Fluorocytosine - DNA Synthesis Inhibitor
5-Fluorocytosine (5-FC) is a fluorinated cytosine analogue, clinically approved as an antifungal agent. 5-FC is nontoxic to mammalian cells due to their lack
of the enzyme cytosine deaminase (CD). CD converts 5-FC into 5-fluorouracil (5-FU), a highly cytotoxic compound routinely used in cancer chemotherapy.
5-FC is used in combination with the E. coli CD gene (codA) or S. cerevisiae CD gene (fcy) in suicide gene therapy protocols 1 .
5-Fluorouracil - Thymidylate Synthase Inhibitor
5-Fluorouracil (5-FU), a fluorinated analogue of uracil, is approved for cancer chemotherapy as an antineoplastic, antimetabolic agent. The cytotoxic effects
of 5-FU occur mainly following its conversion to 5-fluoro-deoxyuridine monophosphate (5-FdUMP), an irreversible inhibitor of thymidylate synthase. This
leads to cell death by DNA synthesis inhibition through deoxythymidine triphosphate deprivation.
Ganciclovir - DNA Synthesis Inhibitor
Ganciclovir (GCV) is a synthetic analogue of 2'-deoxy-guanosine, clinically approved for the treatment of cytomegalovirus (CMV) infections. GCV is used as
a prodrug to obtain a suicide effect in cells transfected with the herpes virus thymidine kinase gene (HSV-tk) 1 . HSV-TK phosphorylates GCV to GCVmonophosphate
which is further converted to GCV-diphosphate and GCV-triphosphate by host kinases. GCV-triphosphate causes premature DNA chain
termination and apoptosis. The HSV-tk gene and ganciclovir are used in molecular biology for negative selection 2 .
1. Aghi M. et al., 2000. Prodrug activation enzymes in cancer gene therapy. J Gene Med. 2(3):148-64. 2. Karreman C., 1998. New positive/negative selectable markers for mammalian cells on
the basis of Blasticidin deaminase-thymidine kinase fusions. Nucleic Acids Res. 26(10):2508-10.
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