Geldanamycin and its derivates - a students review

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<a href="http://www.fermentek.co.il/geldanamycin.htm">Pure geldanamycin is produced by Fermentek in batches 12 kg large</a>


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Introduction

Geldanamycin and derivates thereof are a family of  a benzoquinone ansamycins, antibiotics originally isolated on the basis of their weak antibiotic activity  [1] that were subsequently shown to display potent antitumor activity.

Geldanamycin induces the degradation of proteins that are mutated in tumor cells such as v-src, bcr-abl and p53 preferentially over their normal cellular counterparts. This effect is mediated via HSP90. Despite its potent antitumor potential, Geldanamycin has several major disadvantages as a drug candidate that have led to the development of Geldanamycin analogues, in particular analogues containing a substitution on the 17 position:

17-AAG
17-DMAG
and some others

History

Originally, Geldanamycin was discovered in the broth and the mycelium of Streptomyces sp, by DeBoer et al, and was published 1n 1970 [1].

Rinehart established the structure of Geldanamycin in the same year [2] He went on with his research on Geldanamycin biosynthesis [3], [5]

In 1976 DeBoyer discovered a new bacterial strain, Streptomyces hygroscopicus var. Geldanus [4], capable of making Geldanamycin, Nigericin and two other antibiotics of lesser importance.

From 1973 and on, numerous applied researches were conduct, which did not yield scientific publications but rather patents on miscellaneous semi-synthetic derivates of Geldanamycin.

In 1977 first two papers appear which deal with the antitumor potential of Geldanamycin, both based on in-vitro work: [6] by Rinehart, [7] (continued in 1978: [8]), by Price PJ, Suk WA, Skeen PC, Spahn GJ, Chirigos MA.  In 1982 Tanaka et al added a single publication, [10] again, an in-vitro work. Tanaka showed that Geldanamycin  blocked DNA synthesis rather than  RNA and protein syntheses.

Little or no work was done until 1989, when Yamaki, Ariga [12] found some hints about potential anti-tumor value of this compound. However they emphasized its value as a tool in molecular biology:

Thus, Geldanamycin should be useful to investigate the molecular mechanism of DNA replication promoted by c-myc protein and also to distinguish the function of c-myc protein from that of p53 protein in DNA replication.

In 1993 a major breakthrough was achieved by Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM., who discovered the role of the HSP (heat shock proteins) in the initiation of certain cancers.[13]. Blagosklonny showed [ 15] how Geldanamycin could prevent restructuring of mutated cancer-relevant  proteins such as p53

 In 1995 Geldanamycin was ready for preclinical studies in animals. [14] Immediately attention was paid to the hepatotoxic  properties of geldanamycin. Then it was found that derivatization of Geldanamycin at the position 17, may lead to desired results, such as reduction of hepatotoxic properties, alteration of solubility etc.

For example, US patent no 4261989 claims not less than 34 various derivates of geldanamycin at the 17 th position

The first publication about the 17AAG  told that 17AAG had lower in vivo toxicity than Geldanamycin. Even though HSP90 affinity  to 17AAG was lesser than to Geldanamycin, 17AAG and Geldanamycin gave biologic effects in malignant cells at similar or same concentrations.[16]

It is very interesting though not very surprising, that next 17AAG related publication appeared only in 2000 [17]. The discoverers of 17AAG did not claimed a patent of it.

Another important Geldanamycin derivate, 17DMAG, appeared in 2002 [18]. This compound had better solubility in water, that Geldanamycin.

Miscellaneous applications

[11] Putnam et al researched phytotoxic properties of Geldanamycin and nigericin, in 1986

Patent:

There is no patent on Geldanamycin as a compound.

Geldanamycin

Fermentation

Geldanamycin  is a natural product produced by Streptomyces hygroscopicus in submerged fermentation. InvivoGen claim they make Geldanamycin  from a mutant strain of Streptomyces hygroscopicus, inactivated for the synthesis of Nigericin. The Nigericin is an interesting compound by itself. Fermentek produces Nigericin as a molecular biology reagent.

Fermentek claim they use no mutants, but native unmodified strains only, as a matter of company policy.

Pharmacology

Geldanamycin  binds with high affinity into the ATP binding pocket of Hsp 90. Hsp 90 is a ubiquitous molecular chaperone critical for the folding, assembly and activity of multiple mutated and overexpressed signaling proteins that promote the growth and/or survival of tumor cells. Hsp 90 target  proteins include mutated p53, Raf-1, Akt, ErbB2 and hypoxia-inducible factor 1a (HIF-1a). Binding of Geldanamycin  to Hsp 90 causes the destabilization and degradation of its client proteins.

Formula: C29H40N2O9

Molecular weight: 560.64

CAS Number : 30562-34-6

Appearance: yellow powder

 

 

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[1] DeBoer C, Meulman PA, Wnuk RJ, Peterson DH.   Geldanamycin, a new antibiotic.
J Antibiot (Tokyo). 1970 Sep;23(9):442-7. No abstract available.
PMID: 5459626

[2] Geldanamycin. I. Structure assignment.
J Am Chem Soc. 1970 Dec 30;92(26):7591-3. No abstract available.
PMID: 5490719
[3] Geldanamycin biosynthesis and carbon magnetic resonance.J Am Chem Soc. 1974 May 15;96(10):3316-7.
[4] J Antibiot (Tokyo). 1976 Nov;29(11):1182-8. The description and Geldanamycin  click to see the abstractabout geldanamycin productionproduction of Streptomyces hygroscopicus var. Geldanus.
[5] Rinehart et al, Biosynthetic origin of the C2 units of geldanamycin and distribution of label from D-[6-13C]glucose.
J Am Chem Soc. 1977 May 11;99(10):3541-4.
[6] Effects of geldanamycin and its derivatives on RNA-directed DNA polymerase and infectivity of Rauscher leukemia virus.
Cancer Treat Rep. 1977 Aug;61(5):815-24
[7] Geldanamycin inhibition of 3-methylcholanthrene-induced rat embryo cell transformation.
Proc Soc Exp Biol Med. 1977 Sep;155(4):4
61-3
[8] Preferential inhibition of terminal deoxynucleotidyltransferase activity among deoxyribonucleic acid polymerase activities of leukemic and normal cells by geldanamycin, streptoval C, streptovarone, and dapmavarone. Mol Pharmacol. 1978 May;14(3):442-7
[9] Growth inhibition of virus transformed cells in vitro and antitumor activity in vivo of geldanamycin and its derivatives.J Antibiot (Tokyo). 1979 Aug;32(8):849-51. Sasaki K,  Yasuda H, Onodera K.
[10] geldanamycin invitro antitumor murine cell lineInhibition of DNA synthesis in murine tumor cells by geldanamycin, an antibiotic of the benzoquinoid ansamycin group.
[11] click to see the abstractabout geldanamycin productionHerbicidal effects of geldanamycin and nigericin, antibiotics from Streptomyces hygroscopicus.
[12]  click to see the abstractabout geldanamycin productionInhibition of c-myc gene expression in murine lymphoblastoma cells by geldanamycin and herbimycin, antibiotics of benzoquinoid ansamycin group
click to see the abstract about geldanamycin production[13]  Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8324-8;  Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation.
[14] click to see the abstract about geldanamycin productionPreclinical pharmacologic evaluation of geldanamycin as an antitumor agent
[15]click to see the abstract about geldanamycin production  Geldanamycin selectively destabilizes and conformationally alters mutated p53
[16] The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin.
Cancer Chemother Pharmacol. 1998;42(4):273-9

Schulte TW, Neckers LM.

[17] Modulation of metastasis phenotypes of non-small cell lung cancer cells by 17-allylamino 17-demethoxy geldanamycin.
Ann Thorac Surg. 2000 Dec;70(6):1853-60.
Nguyen DM, Desai S, Chen A, Weiser TS, Schrump DS.
[18] Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats.
Cancer Chemother Pharmacol. 2002 Jan;49(1):7-19.

Eiseman JL.

 
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