KUKOAMINE-A AND OTHER HYDROPHOBIC ACYLPOLYAMINES - POTENT AND SELECTIVE INHIBITORS OF CRITHIDIA-FASCICULATA TRYPANOTHIONE REDUCTASE

被引:80
作者
PONASIK, JA
STRICKLAND, C
FAERMAN, C
SAVVIDES, S
KARPLUS, PA
GANEM, B
机构
[1] CORNELL UNIV, BAKER LAB, DEPT CHEM, ITHACA, NY 14853 USA
[2] CORNELL UNIV, DEPT BIOCHEM MOLEC & CELL BIOL, ITHACA, NY 14853 USA
关键词
D O I
10.1042/bj3110371
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The enzyme trypanothione reductase (TR), together with its substrate, the glutathione-spermidine conjugate trypanothione, plays an essential role in protecting parasitic trypanosomatids against oxidative stress and is a target for drug design. Here we show that a naturally occurring spermine derivative, the antihypertensive agent kukoamine A [(NN12)-N-1-bis(dihydrocaffeoyl)-spermine] inhibits TR as a mixed inhibitor (K-i = 1.8 mu M, K-ii = 13 mu M). Kukoamine shows no significant inhibition of human glutathione reductase (K-i > 10 mM) and thus provides a novel selective drug lead. The corresponding (NN8)-N-1-bis(dihydrocaffeoyl)spermidine derivative was synthesized and acted as a purely competitive inhibitor with K-i=7.5 mu M. A series of mono- and di-acylated spermines and spermidines were synthesized to gain an insight into the effect of polyamine chain length, the nature and position of the acyl substituent and the importance of conformational mobility. These compounds inhibited TR with Ki values ranging from 11 to 607 mu M.
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页码:371 / 375
页数:5
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