N-benzylisatin sulfonamide analogues as potent caspase-3 inhibitors:: Synthesis, in vitro activity, and molecular modeling studies

被引:101
作者
Chu, WH [1 ]
Zhang, J [1 ]
Zeng, CB [1 ]
Rothfuss, J [1 ]
Tu, ZD [1 ]
Chu, YX [1 ]
Reichert, DE [1 ]
Welch, MJ [1 ]
Mach, RH [1 ]
机构
[1] Washington Univ, Sch Med, Div Radiol Sci, St Louis, MO 63110 USA
关键词
D O I
10.1021/jm0506625
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A number of isatin sulfonamide analogues were prepared and their potencies for inhibiting caspase-1, -3, -6, -7, and -8 were evaluated in vitro. Several compounds displaying a nanomolar potency for inhibiting the executioner caspases, caspase-3 and caspase-7, were identified. These compounds were also observed to have a low potency for inhibiting the initiator caspases, caspase-1 and caspase-8, and caspase-6. Molecular modeling studies provided further insight into the interaction of this class of compounds with activated caspase-3. The results of the current study revealed a number of non-peptide-based caspase inhibitors that may be useful in assessing the role of inhibiting the executioner caspases in minimizing tissue damage in disease conditions characterized by unregulated apoptosis.
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收藏
页码:7637 / 7647
页数:11
相关论文
共 24 条
[1]   Novel 3-pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors [J].
Abreo, MA ;
Lin, NH ;
Garvey, DS ;
Gunn, DE ;
Hettinger, AM ;
Wasicak, JT ;
Pavlik, PA ;
Martin, YC ;
DonnellyRoberts, DL ;
Anderson, DJ ;
Sullivan, JP ;
Williams, M ;
Americ, SP ;
Holladay, MW .
JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (04) :817-825
[2]   Reducing the peptidyl features of caspase-3 inhibitors: A structural analysis [J].
Becker, JW ;
Rotonda, J ;
Soisson, SM ;
Aspiotis, R ;
Bayly, C ;
Francoeur, S ;
Gallant, M ;
Garcia-Calvo, M ;
Giroux, A ;
Grimm, E ;
Han, YX ;
McKay, D ;
Nicholson, DW ;
Peterson, E ;
Renaud, J ;
Roy, S ;
Thornberry, N ;
Zamboni, R .
JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (10) :2466-2474
[3]   The Protein Data Bank [J].
Berman, HM ;
Westbrook, J ;
Feng, Z ;
Gilliland, G ;
Bhat, TN ;
Weissig, H ;
Shindyalov, IN ;
Bourne, PE .
NUCLEIC ACIDS RESEARCH, 2000, 28 (01) :235-242
[4]   A Novel nonpeptidic caspase-3/7 inhibitor, (S)-(+)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin reduces myocardial ischemic injury [J].
Chapman, JG ;
Magee, WP ;
Stukenbrok, HA ;
Beckius, GE ;
Milici, AJ ;
Tracey, WR .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2002, 456 (1-3) :59-68
[5]  
*CHEM COMP GROUP, 2004, MOL OP ENV MOE
[6]   Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design [J].
Choong, IC ;
Lew, W ;
Lee, D ;
Pham, P ;
Burdett, MT ;
Lam, JW ;
Wiesmann, C ;
Luong, TN ;
Fahr, B ;
DeLano, WL ;
McDowell, RS ;
Allen, DA ;
Erlanson, DA ;
Gordon, EM ;
O'Brien, T .
JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (23) :5005-5022
[7]   Caspases: Keys in the ignition of cell death [J].
Denault, JB ;
Salvesen, GS .
CHEMICAL REVIEWS, 2002, 102 (12) :4489-4499
[8]   Inhibition of human caspases by peptide-based and macromolecular inhibitors [J].
Garcia-Calvo, M ;
Peterson, EP ;
Leiting, B ;
Ruel, R ;
Nicholson, DW ;
Thornberry, NA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (49) :32608-32613
[9]   Selective, reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic-ischemic brain injury [J].
Han, BH ;
Xu, DG ;
Choi, JJ ;
Han, YX ;
Xanthoudakis, S ;
Roy, S ;
Tam, J ;
Vaillancourt, J ;
Colucci, J ;
Siman, R ;
Giroux, A ;
Robertson, GS ;
Zamboni, R ;
Nicholson, DW ;
Holtzman, DM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (33) :30128-30136
[10]   Discovery of novel aspartyl ketone dipeptides as potent and selective caspase-3 inhibitors [J].
Han, YX ;
Giroux, A ;
Grimm, EL ;
Aspiotis, R ;
Francoeur, S ;
Bayly, CI ;
Mckay, DJ ;
Roy, S ;
Xanthoudakis, S ;
Vaillancourt, JP ;
Rasper, DM ;
Tam, J ;
Tawa, P ;
Thornberry, NA ;
Paterson, EP ;
Garcia-Calvo, M ;
Becker, JW ;
Rotonda, J ;
Nicholson, DW ;
Zamboni, RJ .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (03) :805-808