O'Sullivan M C, Zhou Q, Li Z, Durham T B, Rattendi D, Lane S, Bacchi C J
Department of Chemistry, Indiana State University, Terre Haute 47809, USA.
Bioorg Med Chem. 1997 Dec;5(12):2145-55. doi: 10.1016/s0968-0896(97)00157-0.
Trypanothione reductase (TR) occurs exclusively in trypanosomes and leishmania, which are the etiological agents of many diseases. TR plays a vital role in the antioxidant defenses of these parasites and inhibitors of TR have potential as antitrypanosomal agents. We describe the syntheses of several spermine and spermidine derivatives and the inhibiting effects of these compounds on T. cruzi TR. All of the inhibiting compounds displayed competitive inhibition of TR-mediated reduction of trypanothione disulfide. The three most effective compounds studied were N4,N8-bis(3-phenylpropyl)spermine (12), N4,N8-bis(2-naphthylmethyl)spermine (14), and N1,N8-bis(2-naphthylmethyl)spermidine (21), with Ki values of 3.5, 5.5 and 9.5 microM, respectively. Compounds 12, 14, and 21 were found to be potent trypanocides in vitro with IC50 values ranging from 0.19 to 0.83 microM against four T. brucei ssp. strains. However, these compounds did not prolong the lives of mice infected with trypanosomes. This work indicates that certain polyamine derivatives which target a unique pathway in Trypanosomatidae have potential as antitrypanosomal agents.
谷胱甘肽还原酶（TR）仅存在于锥虫和利什曼原虫中，它们是许多疾病的病原体。TR在这些寄生虫的抗氧化防御中起着至关重要的作用，TR抑制剂有作为抗锥虫药物的潜力。我们描述了几种精胺和亚精胺衍生物的合成以及这些化合物对克氏锥虫TR的抑制作用。所有抑制性化合物均对TR介导的谷胱甘肽二硫化物还原表现出竞争性抑制。研究的三种最有效的化合物是N4，N8-双（3-苯丙基）精胺（12）、N4，N8-双（2-萘甲基）精胺（14）和N1，N8-双（2-萘甲基）亚精胺（21），其Ki值分别为3.5、5.5和9.5 microM。发现化合物12、14和21在体外是有效的杀锥虫剂，对四种布氏锥虫亚种的IC50值范围为0.19至0.83 microM。然而，这些化合物并没有延长感染锥虫的小鼠的寿命。这项工作表明，某些靶向锥虫科独特途径的多胺衍生物有作为抗锥虫药物的潜力。
