Radester, a novel inhibitor of the Hsp90 protein folding machinery

被引：63

作者：

Shen, G

Blagg, BSJ

机构：

[1] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA

[2] Univ Kansas, Ctr Prot Struct & Funct, Lawrence, KS 66045 USA

来源：

ORGANIC LETTERS | 2005年 / 7卷 / 11期

关键词：

D O I：

10.1021/ol050580a

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

The antitumor antibiotics radicicol and geldanamycin are potent inhibitors of the Hsp90 protein folding machinery. Radester is a hybrid composed of radicicol's resorcinol ring and geldanamycin's quinone through an isopropyl ester. Radester was prepared, and the cytotoxicity of it and the corresponding hydroquinone were determined in MCF-7 breast cancer cells to be 13.9 and 7.1 mu M, respectively. Protein degradation assays were performed on Hsp90-dependent client proteins, Her-2 and Raf, to correlate Hsp90 inhibition to cytotoxicity.

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收藏

页码：2157 / 2160

页数：4

相关论文

共 18 条

[1] New agents in cancer clinical trials [J].

Adams, J ;

Elliott, PJ .

ONCOGENE, 2000, 19 (56) :6687-6692

[2] Selective synthesis of the para-quinone region of geldanamycin [J].

Andrus, MB ;

Hicken, EJ ;

Meredith, EL ;

Simmons, BL ;

Cannon, JF .

ORGANIC LETTERS, 2003, 5 (21) :3859-3862

[3] Heat shock protein-chaperoned peptides but not free peptides introduced into the cytosol are presented efficiently by major histocompatibility complex I molecules [J].

Binder, RJ ;

Blachere, NE ;

Srivastava, PK .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (20) :17163-17171

[4] Hsp90: the vulnerable chaperone [J].

Chiosis, G ;

Vilenchik, M ;

Kim, J ;

Solit, D .

DRUG DISCOVERY TODAY, 2004, 9 (20) :881-888

[5] Design, synthesis, and evaluation of a radicicol and geldanamycin chimera, radamide [J].

Clevenger, RC ;

Blagg, BSJ .

ORGANIC LETTERS, 2004, 6 (24) :4459-4462

[6] NITRATIONS AND OXIDATIONS WITH INORGANIC NITRATE SALTS IN TRIFLUOROACETIC-ANHYDRIDE [J].

CRIVELLO, JV .

JOURNAL OF ORGANIC CHEMISTRY, 1981, 46 (15) :3056-3060

[7] Geldanamycin leads to superoxide formation by enzymatic and non-enzymatic redox cycling - Implications for studies of hsp90 and endothelial cell nitric-oxide synthase [J].

Dikalov, S ;

Landmesser, U ;

Harrison, DG .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (28) :25480-25485

[8] A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors [J].

Kamal, A ;

Thao, L ;

Sensintaffar, J ;

Zhang, L ;

Boehm, MF ;

Fritz, LC ;

Burrows, FJ .

NATURE, 2003, 425 (6956) :407-410

[9] Crystal structures of human HSP90α-complexed with dihydroxyphenylpyrazoles [J].

Kreusch, A ;

Han, SL ;

Brinker, A ;

Zhou, V ;

Choi, HS ;

He, Y ;

Lesley, SA ;

Caldwell, J ;

Gu, XJ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (05) :1475-1478

[10] ROUTES TO MITOMYCINS - AN IMPROVED SYNTHESIS OF 7-METHOXYMITOSENE USING PALLADIUM CATALYSIS [J].

LULY, JR ;

RAPOPORT, H .

JOURNAL OF ORGANIC CHEMISTRY, 1984, 49 (09) :1671-1672