Inhibitors of Sir2: Evaluation of splitomicin analogues

被引：154

作者：

Posakony, J ^{[1
]}

Hirao, M ^{[1
]}

Stevens, S ^{[1
]}

Simon, JA ^{[1
]}

Bedalov, A ^{[1
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Clin Res & Human Biol Div, Seattle, WA 98109 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 10期

关键词：

D O I：

10.1021/jm030473r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Splitomicin (1) and 41 analogues were prepared and evaluated in cell-based Sir2 inhibition and toxicity assays and an in vitro Sir2 inhibition assay. Lactone ring or naphthalene (positions 7-9) substituents decrease activity, but other naphthalene substitutions (positions 5 and 6) are well-tolerated. The hydrolytically unstable aromatic lactone is important for activity. Lactone hydrolysis rates were used as a measure of reactivity; hydrolysis rates correlate with inhibitory activity. The most potent Sir2 inhibitors were structurally similar to and had hydrolysis rates similar to 1.

引用

页码：2635 / 2644

页数：10

共 18 条

[1] Mutations in Saccharomyces cerevisiae gene SIR2 can have differential effects on in vivo silencing phenotypes and in vitro histone deacetylation activity [J].

Armstrong, CM ;

Kaeberlein, M ;

Imai, SI ;

Guarente, L .

MOLECULAR BIOLOGY OF THE CELL, 2002, 13 (04) :1427-1438

[2] Identification of a small molecule inhibitor of Sir2p [J].

Bedalov, A ;

Gatbonton, T ;

Irvine, WP ;

Gottschling, DE ;

Simon, JA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (26) :15113-15118

[3] Acetylation inactivates the transcriptional repressor BCL6 [J].

Bereshchenko, OR ;

Gu, W ;

Dalla-Favera, R .

NATURE GENETICS, 2002, 32 (04) :606-613

[4] TRANSCRIPTIONAL SILENCING IN YEAST IS ASSOCIATED WITH REDUCED NUCLEOSOME ACETYLATION [J].

BRAUNSTEIN, M ;

ROSE, AB ;

HOLMES, SG ;

ALLIS, CD ;

BROACH, JR .

GENES & DEVELOPMENT, 1993, 7 (04) :592-604

[5] DIRECT LITHIATION OF HYDROXYAROMATICS [J].

COLL, G ;

MOREY, J ;

COSTA, A ;

SAA, JM .

JOURNAL OF ORGANIC CHEMISTRY, 1988, 53 (22) :5345-5348

[6] POSITION EFFECT AT SACCHAROMYCES-CEREVISIAE TELOMERES - REVERSIBLE REPRESSION OF POL-II TRANSCRIPTION [J].

GOTTSCHLING, DE ;

APARICIO, OM ;

BILLINGTON, BL ;

ZAKIAN, VA .

CELL, 1990, 63 (04) :751-762

[7] Deacetylase enzymes: biological functions and the use of small-molecule inhibitors [J].

Grozinger, CM ;

Schreiber, SL .

CHEMISTRY & BIOLOGY, 2002, 9 (01) :3-16

[8] Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening [J].

Grozinger, CM ;

Chao, ED ;

Blackwell, HE ;

Moazed, D ;

Schreiber, SL .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (42) :38837-38843

[9] Identification of selective inhibitors of NAD+-dependent deacetylases using phenotypic screens in yeast [J].

Hirao, M ;

Posakony, J ;

Nelson, M ;

Hruby, H ;

Jung, MF ;

Simon, JA ;

Bedalov, A .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (52) :52773-52782

[10] Translating the histone code [J].

Jenuwein, T ;

Allis, CD .

SCIENCE, 2001, 293 (5532) :1074-1080

← 1 2 →