Synthesis and characterization of an N-acylsulfonamide inhibitor of human asparagine synthetase

被引：39

作者：

Koroniak, L ^{[1
]}

Ciustea, M ^{[1
]}

Gutierrez, JA ^{[1
]}

Richards, NGJ ^{[1
]}

机构：

[1] Univ Florida, Dept Chem, Gainesville, FL 32611 USA

来源：

ORGANIC LETTERS | 2003年 / 5卷 / 12期

关键词：

D O I：

10.1021/ol034212n

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

The synthesis of N-acylsulfonamide 6, which is an analogue of beta-aspartyl-AMP, is described. This compound appears to be the first and only potent inhibitor of human asparagine synthetase that has been described to date. The N-acylsulfonamide 6 exhibits slow-onset inhibition kinetics, with a K-1* of 728 nM. Preparation and characterization of two additional N-acylsulfonamide analogues has also demonstrated the importance of hydrogen-bonding interactions in the recognition of the AS inhibitor with the enzyme. These observations provide the basis for the discovery of new compounds with application in the treatment of drug-resistant leukemia.

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页码：2033 / 2036

页数：4

相关论文

共 33 条

[1] Asparagine synthetase expression alone is sufficient to induce L-asparaginase resistance in MOLT-4 human leukaemia cells [J].

Aslanian, AM ;

Fletcher, BS ;

Kilberg, MS .

BIOCHEMICAL JOURNAL, 2001, 357 :321-328

[2] Kinetic mechanism of Escherichia coli asparagine synthetase B [J].

Boehlein, SK ;

Stewart, JD ;

Walworth, ES ;

Thirumoorthy, R ;

Richards, NGJ ;

Schuster, SM .

BIOCHEMISTRY, 1998, 37 (38) :13230-13238

[3]

BOEHLEIN SK, 1994, J BIOL CHEM, V269, P26789

[4] Characterization of inhibitors acting at the synthetase site of Escherichia coli asparagine synthetase B [J].

Boehlein, SK ;

Nakatsu, T ;

Hiratake, J ;

Thirumoorthy, R ;

Stewart, JD ;

Richards, NGJ ;

Schuster, SM .

BIOCHEMISTRY, 2001, 40 (37) :11168-11175

[5] Rational design of femtomolar inhibitors of isoleucyl tRNA synthetase from a binding model for pseudomonic acid-A [J].

Brown, MJB ;

Mensah, LM ;

Doyle, ML ;

Broom, NJP ;

Osbourne, N ;

Forrest, AK ;

Richardson, CM ;

O'Hanlon, PJ ;

Pope, AJ .

BIOCHEMISTRY, 2000, 39 (20) :6003-6011

[6] Molecular recognition of tyrosinyl adenylate analogues by prokaryotic tyrosyl tRNA synthetases [J].

Brown, P ;

Richardson, CM ;

Mensah, LM ;

O'Hanlon, PJ ;

Osborne, NF ;

Pope, AJ ;

Walker, G .

BIOORGANIC & MEDICINAL CHEMISTRY, 1999, 7 (11) :2473-2485

[7]

Chakrabarti R, 1997, INT J PEDIAT HEM ONC, V4, P597

[8] REGULATORS OF THE METABOLISM OF L-ASPARAGINE - A SEARCH FOR ENDOGENOUS INHIBITORS [J].

COONEY, DA ;

JONES, MT ;

MILMAN, HA ;

YOUNG, DM ;

JAYARAM, HN .

INTERNATIONAL JOURNAL OF BIOCHEMISTRY, 1980, 11 (06) :519-539

[9]

COONEY DA, 1976, CANCER TREAT REP, V60, P1493

[10] A concise synthesis of β-asparaginyladenylate [J].

Ding, Y ;

Wang, JQ ;

Schuster, SM ;

Richards, NGJ .

JOURNAL OF ORGANIC CHEMISTRY, 2002, 67 (12) :4372-4375

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