Geldanamycin

Geldanamycin

Names
IUPAC names (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 (Jmol)	Interactive image
ChEMBL	ChEMBL278315 Y
ChemSpider	10272739 Y
DrugBank	DB02424 Y
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  (what is YN ?)
Infobox references

-8,14,19-trimethoxy-4,10,12,16-tetramethyl
-3,20,22-trioxo-2-azabicyclo[16.3.1]

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. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.

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 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. These side effects have led to the development of geldanamycin analogues, in particular analogues containing a derivatisation at the 17 position:

Geldanamycin was originally discovered in the organism Streptomyces hygroscopicus. 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. 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.