Synergistic effects of geldanamycin and antitumor drugs.

Geldanamycin kháng Bel-7402

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Geldanamycin

Names
IUPAC name (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate
Identifiers
CAS Number	30562-34-6
3D model (JSmol)	Interactive image
ChemSpider	10272739
DrugBank	DB02424
PubChem CID	5288382
InChI[show]
SMILES[show]
Properties
Chemical formula	C29H40N2O9
Molar mass	560.64 g/mol
Appearance	Gold-yellow fine crystalline powder
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Geldanamycin is a 1,4-benzoquinone ansamycin antitumor antibiotic that inhibits the function of Hsp90 (Heat Shock Protein 90) by binding to the unusual ADP/ATP-binding pocket of the protein.^[1] HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.

Hsp90-geldanamycin complex. PDB 1yet^[2]

Geldanamycin induces the degradation of proteins that are mutated in tumor cells such as v-Src, Bcr-Abl and p53preferentially over their normal cellular counterparts. This effect is mediated via HSP90. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a drug candidate such as hepatotoxicity, further, Jilani et al. reported that geldanamycin induces the apoptosis of erythrocytes under physiological concentrations.^[3] These side effects have led to the development of geldanamycin analogues, in particular analogues containing a derivatisation at the 17 position:

• 17-AAG
• 17-DMAG

Contents

  [hide] 

• 1Biosynthesis
• 2Notes
• 3References
• 4External links

Biosynthesis[edit]

Geldanamycin was originally discovered in the organism Streptomyces hygroscopicus.^[4] It is a macrocyclic polyketide that is synthesized by a Type I polyketide synthase. The genes gelA, gelB, and gelC encode for the polyketide synthase. The PKS is first loaded with 3-amino-5-hydroxybenzoic acid (AHBA). It then utilizes malonyl-CoA, methylmalonyl-CoA, and methoxymalonyl-CoA to synthesize the precursor molecule Progeldanamycin.^[5] This precursor is subjected to several enzymatic and non-enzymatic tailoring steps to produce the active molecule Geldanamycin, which include hydroxylation, o-methylation, carbamoylation, and oxidation.^[6]