Metal compounds for the treatment of parasitic diseases
Metal compounds for the treatment of parasitic diseases
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DOI：
10.1016/j.jinorgbio.2008.05.010
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发表时间：
2008-10-01
影响因子：
3.9
通讯作者：
McKerrow, James H.
中科院分区：
文献类型：
--
作者：
Fricker, Simon P.;Mosi, Renee M.;McKerrow, James H.
锥虫寄生原生动物的半胱氨酸蛋白酶已被证实为恰加斯病和利什曼病的化疗靶点。金、铂、铱、钯、铑和锇的金属络合物已被报道对多种锥虫具有活性，但这些化合物的分子靶点尚未确定。研究了金（III）和钯（II）环化配合物以及氧合铼（V）配合物对哺乳动物和寄生虫半胱氨酸蛋白酶的活性。所有金（III）配合物（1-6）抑制组织蛋白酶B，IC 50值在0.2-1.4 μ M范围内。在六种钯化合物中，乙酰基[2，6-双[（丁基硫代-kappa S）甲基]苯基-kappa C]-，（SP-4-3）-钯（II）（11）是组织蛋白酶B的最有效抑制剂，IC 50为0.4 μ M。观察到氧合铼（V）与氯[2，2 ′-（硫代-κ S）bisethanethiolato-KS）II氧合铼（V）（16）的络合物是组织蛋白酶B的最有效抑制剂，IC 50为0.009 μ M，具有明确的结构-活性关系。进一步测试了六种复合物对寄生虫半胱氨酸蛋白酶、来自克氏锥虫的cruzain和来自L.少校;最有效的抑制剂是两种氯代络合物（2（1H）-吡啶硫代-κ S-2）[2，6-双[（巯基-κ S）甲基]吡啶-κ N-1]氧合铼（V）（15）和氯代[2，2 ′-（硫代-κ S）双[乙硫醇基-κ S）]]氧合铼（V）（16）。还在寄生虫生长测定中评价了化合物。两种氧合铼（V）化合物（（p-甲氧基苯基硫代-S）[2，6-双（巯基-kappa S）甲基吡啶-kappa N-1]氧合铼（V）（14）和（甲硫基）12，2 ′-（硫代-kappa S）双[乙硫基-kappa S）]]氧合铼（V）（18）和钯化合物11抑制T. cruzi细胞内生长，并且化合物11抑制三种利什曼原虫属物种中的前鞭毛体生长。总之，该初步数据表明，靶向寄生虫半胱氨酸蛋白酶的金属络合物显示出治疗恰加斯病和利什曼病的前景。(c)2008年由Elsevier Inc.出版
The cysteine proteases of the trypanosomatid parasitic protozoa have been validated as targets for chemotherapy of Chagas' disease and leishmaniasis. Metal complexes of gold, platinum, iridium, palladium, rhodium and osmium have been reported to have activity against a variety of trypanosomatids, but the molecular target of these compounds has not been defined. The activity of gold(III) and palladium(II) cyclometallated complexes, and oxorhenium(V) complexes against mammalian and parasitic cysteine proteases was investigated. All gold(III) complexes (1-6) inhibited cathepsin B with IC50 values in the range of 0.2-1.4 mu M. Of the six palladium compounds, aceto[2,6-bis[(butylthio-kappa S)methyl]phenyl-kappa C]-, (SP-4-3)-palladium(II) (11) was the most potent inhibitor of cathepsin B with an IC50 of 0.4 mu M. A clear structure-activity relationship was observed with the oxorhenium(V) complexes with chloro[2,2'-(thio-kappa S)bislethanethiolato-KS)II oxorhenium(V) (16) being the most potent inhibitor of cathepsin B with an IC50 of 0.009 mu M. Six complexes were further tested against the parasite cysteine proteases, cruzain from T cruzi, and cpB from L. major; the most potent inhibitors were the two rhenium complexes (2(1H)-pyridinethionato-kappa S-2)[2,6-bis[(mercapto-kappa S)methyllpyridine-kappa N-1] oxorhenium(V) (15) and chloro[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium(V) (16). The compounds were also evaluated in assays for parasite growth. Two oxorhenium(V) compounds ((p-methoxyphenylthiolato-S)[2,6-bisl(mercapto-kappa S)methylipyridine-kappa N-1] oxorhenium(V) (14) and (methanethiolato)12,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium (V) (18)) and the palladium compound 11 inhibited T. cruzi intracellular growth, and compound 11 inhibited promastigote growth in three Leishmainia species. In conclusion this preliminary data indicates that metal complexes targeted at parasite cysteine proteases show promise for the treatment of both Chagas' disease and leishmaniasis. (c) 2008 Published by Elsevier Inc.