title: Metal compounds for the treatment of parasitic diseases.
abstract: 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 IC(50) values in the range of 0.2-1.4 microM. 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 IC(50) of 0.4 microM. A clear structure-activity relationship was observed with the oxorhenium(V) complexes with chloro[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium(V) (16) being the most potent inhibitor of cathepsin B with an IC(50) of 0.009 microM. 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)methyl]pyridine-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-bis[(mercapto-kappa S)methyl]pyridine-kappa N(1)] oxorhenium(V) (14) and (methanethiolato)[2,2'-(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 Leishmania 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.
authors.affiliation: Genzyme Corporation, 49 New York Avenue, P.O. Box 9322, Framingham, MA 01701-9322, USA. simon.fricker@genzyme.com
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fricker
authors.forename: Renee M
authors.initials: RM
authors.lastname: Mosi
authors.forename: Beth R
authors.initials: BR
authors.lastname: Cameron
authors.forename: Ian
authors.initials: I
authors.lastname: Baird
authors.forename: Youngbao
authors.initials: Y
authors.lastname: Zhu
authors.forename: Virginia
authors.initials: V
authors.lastname: Anastassov
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cox
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Doyle
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hansell
authors.forename: Gloria
authors.initials: G
authors.lastname: Lau
authors.forename: Jonathan
authors.initials: J
authors.lastname: Langille
authors.forename: Micki
authors.initials: M
authors.lastname: Olsen
authors.forename: Ling
authors.initials: L
authors.lastname: Qin
authors.forename: Renato
authors.initials: R
authors.lastname: Skerlj
authors.forename: Rebecca S Y
authors.initials: RS
authors.lastname: Wong
authors.forename: Zefferino
authors.initials: Z
authors.lastname: Santucci
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014355:Chagas Disease / Q000188:drug therapy*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007287:Inorganic Chemicals / Q000737:chemistry / Q000494:pharmacology; D007891:Leishmania / Q000187:drug effects*; D007896:Leishmaniasis / Q000188:drug therapy*; D008670:Metals / Q000494:pharmacology* / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014345:Trypanosoma / Q000187:drug effects*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007287:Inorganic Chemicals; D008670:Metals; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; D002401:Cathepsin B