Metal compounds for the treatment of parasitic diseases

被引：142

作者：

Fricker, Simon P. ^{[1
]}

Mosi, Renee M. ^{[2
]}

Cameron, Beth R. ^{[2
]}

Baird, Ian ^{[2
]}

Zhu, Youngbao ^{[2
]}

Anastassov, Virginia ^{[2
]}

Cox, Jennifer ^{[2
]}

Doyle, Patricia S. ^{[3
,4
]}

Hansell, Elizabeth ^{[3
,4
]}

Lau, Gloria ^{[2
]}

Langille, Jonathan ^{[2
]}

Olsen, Micki ^{[2
]}

Qin, Ling ^{[2
]}

Skerlj, Renato ^{[1
]}

Wong, Rebecca S. Y. ^{[2
]}

Santucci, Zefferino ^{[2
]}

McKerrow, James H. ^{[3
,4
]}

机构：

[1] Genzyme Corp, Framingham, MA 01701 USA

[2] AnorMED Inc, Langley, BC V2Y 1N5, Canada

[3] Univ Calif San Francisco, Dept Pathol, Trop Dis Res Unit, San Francisco, CA 94143 USA

[4] Univ Calif San Francisco, Sandler Ctr Basic Res Parasit Dis, San Francisco, CA 94143 USA

来源：

JOURNAL OF INORGANIC BIOCHEMISTRY | 2008年 / 102卷 / 10期

关键词：

Au(III) compounds; Pd(II) compounds; oxorhenium(V) compounds; cysteine protease; parasitic diseases;

D O I：

10.1016/j.jinorgbio.2008.05.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

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.

引用

页码：1839 / 1845

页数：7

共 42 条

[1]

A new cruzipain-mediated pathway of human cell invasion by Trypanosoma cruzi requires trypomastigote membranes [J].