64202-81-9

Usage

Uses

Used in Pharmaceutical Industry:
17-Aminodemethoxygeldanamycin is used as a therapeutic agent for targeting specific protein-protein interactions in various diseases, particularly cancer. Its ability to inhibit heat shock protein 90 (Hsp90) makes it a potential candidate for the treatment of cancer cells that rely on this protein for their survival and proliferation.
Used in Anticancer Applications:
In the field of oncology, 17-Aminodemethoxygeldanamycin is used as an anticancer agent, targeting the Hsp90 protein that plays a crucial role in the survival and proliferation of cancer cells. By inhibiting Hsp90, it can lead to the degradation of its client proteins, which are often overexpressed in cancer cells, thus disrupting the cellular processes that support tumor growth and progression.
Used in Drug Delivery Systems:
To enhance the bioavailability, delivery, and therapeutic outcomes of 17-Aminodemethoxygeldanamycin, various drug delivery systems have been developed. These systems, including organic and metallic nanoparticles, aim to improve the solubility, stability, and targeted delivery of the compound, ultimately increasing its efficacy against cancer cells and reducing potential side effects.

InChI:InChI=1/C28H39N3O8/c1-14-10-18-23(29)20(32)13-19(25(18)34)31-27(35)15(2)8-7-9-21(37-5)26(39-28(30)36)17(4)12-16(3)24(33)22(11-14)38-6/h7-9,12-14,16,21-22,24,26,33H,10-11,29H2,1-6H3,(H2,30,36)(H,31,35)/b9-7+,15-8-,17-12+/t14-,16-,21-,22-,24-,26-/m1/s1

Upstream product

• 30562-34-6 geldanmycin 
• 75747-14-7 17-allylamino-17-demethoxygeldanamycin 

Downstream Products

• 157831-11-3 17-amino-22-(4'-aminophenacyl)-17-demethoxygeldanamycin 
• 157831-12-4 17-amino-22-(4'-amino-3'-iodophenacyl)-17-demethoxygeldanamycin 

Relevant academic research and scientific papers

Geldanamycin derivatives and neuroprotective effect on cultured P19-derived neurons

Geldanamycin (1), an antifungal and anticancer ansamycin, was reported as a neurotrophic and neuroprotective substance against antineoplastic drugs, paclitaxel, vincristine, and cisplatin, on cultured dorsal root ganglion neurons from chick embryos. In this study, 1 in a large quantity, together with a known 17-O-demethylgeldanamycin (2), and a new 17-O-demethylgeldanamycin hydroquinone (3) were obtained from a mangrove Streptomyces sp. A series of O-alkyl and N-alkyl derivatives of 1 were prepared by modification of C-17 and/or C-19 on the quinone ring and were evaluated for in vitro activity against P19-derived neurons. Compound 1 and 19-O-methylgeldanamycin (7) at a very low dose (1 nM) enhanced survival and neurite outgrowth of P19-derived neurons and prevented neurotoxicity of paclitaxel and vinblastine. Compound 7, possessing the lowest cytotoxicity and neurotoxicity, is serving as the most promising candidate in neurodegenerative therapy against neurotoxic anticancer drugs.

In vitro metabolism of 17-(dimethylaminoethylamino)-17- demethoxygeldanamycin in human liver microsomes

The objective of this study was to investigate the oxidative metabolism pathways of 17-(dimethylaminoethylamino)-17-demethoxy-geldanamycin (17-DMAG), a geldanamycin (GA) derivative and 90-kDa heat shock protein inhibitor. In vitro metabolic profiles of 17-DMAG were examined by using pooled human liver microsomes (HLMs) and recombinant CYP450 isozymes in the presence or absence of reduced GSH. In addition to 17-DMAG hydroquinone and 19-glutathionyl 17-DMAG, several oxidative metabolites of 17-DMAG were detected and characterized by liquid chromatography-tandem mass spectrometry. Different from previously reported primary biotransformations of GA and GA derivatives, 17-DMAG was not metabolized primarily through the reduction of benzoquinone and GSH conjugation in HLMs. In contrast, the primary biotransformations of 17-DMAG in HLMs were hydroxylation and demethylation on its side chains. The most abundant metabolite was produced by demethylation from the methoxyl at position 12. The reaction phenotyping study showed that CYP3A4 and 3A5 were the major cytochrome P450 isozymes involved in the oxidative metabolism of 17-DMAG, whereas CYP2C8, 2D6, 2A6, 2C19, and 1A2 made minor contributions to the formation of metabolites. On the basis of the identified metabolite profiles, the biotransformation pathways for 17-DMAG in HLMs were proposed. Copyright

ANSAMYCIN HYDROQUINONE COMPOSITIONS

Aspects of the present invention provide compositions comprising a sulfur containing compound and a compound of the formula (I); and also provide methods of their preparation and use.

Hydroquinone Ansamycin Formulations

Pharmaceutical compositions of hydroquinone geldanamycin analogs, and uses of such compositions, are provided.

Ansamycin formulations and methods of use thereof

Provided herein, inter alia, are solid forms of geldanamycin analogs, pharmaceutical compositions comprising a geldanamycin analog and a crystallization inhibitor, methods of making and using such compositions. Additionally, provided are methods for the treatment of cancer, a neoplastic disease state and/or a hyperproliferative disorder, and methods of inhibiting Heat Shock Protein 90 (“Hsp90”).

METHODS AND COMPOSITIONS FOR ENZYME-SPECIFIC ACTIVATION OF CARBOHYDRATE-CONJUGATED PRODRUGS

Methods for the targeted activation of prodrugs by enzymes, which cleave a linkage between a carbohydrate conjugate and a drug. Means to target the activation of prodrugs to specific cells by linking the enzyme to an antibody molecule. Carbohydrate conjugates of geldanamycin.

GELDANAMYCIN AND DERIVATIVES INHIBIT CANCER INVASION AND IDENTIFY NOVEL TARGETS

Geldanamycin derivatives that block the uPA-plasmin network and inhibit growth and invasion by glioblastoma cells and other tumors at femtomolar concentrations are potentially highly active anti-cancer drugs. GA and various 17-amino-17-demethoxygelddanamycin derivatives are disclosed that block HGF/SF-mediated Met tyrosine kinase receptor-dependent uPA activation at fM levels. Other ansamycins (macbecins I and II), GA derivatives, and radicicol required concentrations several logs higher (≥nM) to achieve such inhibition. The inhibitory activity of tested compounds was discordant with the known ability of drugs of this class to bind to hsp90, indicating the existence of a novel target(s) for HGF/SF -mediated events in tumor development. Methods of using such compounds to inhibit cancer cell activities and to treat tumors are disclosed. Such treatment with low doses of these highly active compounds provide an option for treating various Met-expressing tumors, in particular invasive brain cancers, either alone or in combination with conventional surgery, chemotherapy, or radiotherapy.

Structure-based design of 7-carbamate analogs of geldanamycin

The 7-carbamate groups of geldanamycin and its 17-(2-dimethylaminoethyl) amino-17-demethoxy derivative (17-DMAG) bind the N-terminal domain of Hsp90 by establishing a network of hydrogen bonds which involve four buried water molecules. In this study, a structure-based approach was used to investigate the effects of displacing some of these waters by modification of the 7-carbamate. A general loss of binding to human Hsp90 was observed, except for replacement of the carbamate with a hydroxamate group which gave an analog with weak activity. Modeling of Hsp90-ligand interactions suggested that the hydroxamate was not able to displace the buried water molecules, while bulkier substituents able to do so proved inactive.

ANALOGS OF BENZOQUINONE-CONTAINING ANSAMYCINS FOR THE TREATMENT OF CANCER

The present invention provides analogs of benzoquinone-containing ansamycins and uses thereof for treating and modulating disorders associated with hyperproliferation, such as cancer ( formula (I) and (IV). The present invention provides analogs of benzoquinone-containing ansamycins where the benzoquinone is reduced to a hydroquinone and trapped by reaction with a suitable acid, preferably ones that increase the solubility and air stability of the resulting (17)--ammonium hydroquinone ansamycin analog.

Synthesis and biological activities of novel 17-aminogeldanamycin derivatives

A library of over sixty 17-alkylamino-17-demethoxygeldanamycin were synthesized. Their affinity for Hsp90, ability to inhibit growth of SKBr3 mammalian cells, and in selected cases, water solubility, were measured. The structure-activity relationships of binding affinity to Hsp90 and cytotoxicity in SKBr3 cells are discussed. Geldanamycin interferes with the action of heat shock protein 90 (Hsp90) by binding to the N-terminal ATP binding site and inhibiting an essential ATPase activity. In a program directed toward finding potent, water soluble inhibitors of Hsp90, we prepared a library of over sixty 17-alkylamino-17-demethoxygeldanamycin analogs, and compared their affinity for Hsp90, ability to inhibit growth of SKBr3 mammalian cells, and in selected cases, water solubility. Over 20 analogs showed cell growth inhibition potencies similar to that of 17-allylamino-17-demethoxygeldanamycin (17-AAG), the front-runner geldanamycin analog that is currently in multiple clinical trials. Many of these analogs showed water solubility properties that were desirable for formulation. One of the most potent and water-soluble analogs in the series was 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin (17-DMAG), which was independently prepared by the NCI and will soon enter clinical trials. Importantly, the binding affinity of these analogs to the molecular target Hsp90 does not correlate well with their cytotoxicity in SKBr3 cells.