Geldanamycin

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.^[2]

Hsp90-geldanamycin complex. PDB 1yet^[3]

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 Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:5292 Y
ChEMBL	ChEMBL278315 Y
ChemSpider	10272739 Y
DrugBank	DB02424 Y
PubChem CID	5288382
UNII	Z3K3VJ16KU Y
CompTox Dashboard (EPA)	DTXSID7042691
InChI InChI=1S/C29H40N2O9/c1-15-11-19-25(34)20(14-21(32)27(19)39-7)31-28(35)16(2)9-8-10-22(37-5)26(40-29(30)36)18(4)13-17(3)24(33)23(12-15)38-6/h8-10,13-15,17,22-24,26,33H,11-12H2,1-7H3,(H2,30,36)(H,31,35)/b10-8-,16-9+,18-13+/t15-,17+,22+,23+,24-,26+/m1/s1 Y Key: QTQAWLPCGQOSGP-KSRBKZBZSA-N Y InChI=1S/C29H40N2O9/c1-15-11-19-25(34)20(14-21(32)27(19)39-7)31-28(35)16(2)9-8-10-22(37-5)26(40-29(30)36)18(4)13-17(3)24(33)23(12-15)38-6/h8-10,13-15,17,22-24,26,33H,11-12H2,1-7H3,(H2,30,36)(H,31,35)/b10-8-,16-9+,18-13+/t15-,17+,22+,23+,24-,26+/m1/s1 Key: QTQAWLPCGQOSGP-KSRBKZBZBP Key: QTQAWLPCGQOSGP-KSRBKZBZSA-N
SMILES NC(=O)O[C@H]1C(/C)=C/[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)C\C2=C(/OC)C(=O)\C=C(\NC(=O)C(\C)=C\C=C/[C@@H]1OC)C2=O
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). Y verify (what is YN ?) Infobox references

Geldanamycin induces the degradation of proteins that are mutated or overexpressed in tumor cells such as v-Src, Bcr-Abl, p53, and ERBB2. 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.^[4] 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

Biosynthesis

Geldanamycin was originally discovered in the organism Streptomyces hygroscopicus.^[5] 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.^[6] 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.^[7]