IntroductionGeldanamycin 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.FermentationGeldanamycin 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.
PharmacologyGeldanamycin 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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