Design, Synthesis, and Biological Evaluation of Conformationally Constrained cis-Amide Hsp90 Inhibitors

被引：24

作者：

Duerfeldt, Adam S. ^{[1
]}

Brandt, Gary E. L. ^{[1
]}

Blagg, Brian S. J. ^{[1
]}

机构：

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

来源：

ORGANIC LETTERS | 2009年 / 11卷 / 11期

关键词：

MOLECULAR CHAPERONES; CHIMERIC INHIBITORS; TUMOR SELECTIVITY; BINDING-SITE; GELDANAMYCIN; PROTEIN; RADICICOL; TARGET; CANCER; EXPLANATION;

D O I：

10.1021/ol900783m

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

Conformationally constrained cis-amide chimeric inhibitors of Hsp90 have been synthesized and evaluated for their Hsp90 inhibitory activity. These new compounds exhibited Hsp90 ATPase inhibition and induced Hsp90-dependent client protein degradation in a dose-dependent manner. Biological data reported herein suggests that amide bond isomerization of geldanamycin derivatives plays an important role in affinity for the heteroprotein complex present in cancer cells.

引用

页码：2353 / 2356

页数：4

共 31 条

[1] Development and optimization of a useful assay for determining Hsp90's inherent ATPase activity [J].

Avila, C ;

Kornilayev, BA ;

Blagg, BSJ .

BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (04) :1134-1142

[2] 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

[3] Hsp90 as a target for drug development [J].

Chaudhury, Subhabrata ;

Welch, Timothy R. ;

Blagg, Brian S. J. .

CHEMMEDCHEM, 2006, 1 (12) :1331-+

[4]

Chiosis G, 2003, MOL CANCER THER, V2, P123

[5] Tumor selectivity of Hsp90 inhibitors: The explanation remains elusive [J].

Chiosis, Gabriela ;

Neckers, Len .

ACS CHEMICAL BIOLOGY, 2006, 1 (05) :279-284

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

Clevenger, RC ;

Blagg, BSJ .

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

[7] The human cytosolic molecular chaperones hsp90, Hsp70 (hsc70) and hdj-1 have distinct roles in recognition of a non-native protein and protein refolding [J].

Freeman, BC ;

Morimoto, RI .

EMBO JOURNAL, 1996, 15 (12) :2969-2979

[8]

Hadden MK, 2006, CURR TOP MED CHEM, V6, P1173

[9] RHODIUM CARBENOID O-H INSERTION REACTIONS WITH PHENOLS - A FACILE METHOD FOR THE SYNTHESIS OF TRIALKYL 2-ARYLOXYPHOSPHONOACETATES AND THEIR USE IN THE PREPARATION OF 2-ARYLOXY-3-PHENYLPROPANOATES [J].

HAIGH, D .

TETRAHEDRON, 1994, 50 (10) :3177-3194

[10] The hallmarks of cancer [J].

Hanahan, D ;

Weinberg, RA .

CELL, 2000, 100 (01) :57-70

← 1 2 3 4 →