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The mechanism of antimalarial action of the ruthenium (II)-chloroquine complex [RuCl2(CQ)]2
| Content Provider | PubMed Central |
|---|---|
| Author | Martínez, Alberto Rajapakse, Chandima S. K. Becky, Naoulou Kopkalli, Yasemin Davenport, Lesley Sánchez-delgado, Roberto A. |
| Abstract | The mechanism of antimalarial action of the ruthenium-chloroquine complex [RuCl2(CQ)]2 (1), previously shown by us to be active in vitro against CQ-resistant strains of Plasmodium falciparum and in vivo against P. berghei, has been investigated. The complex is rapidly hydrolyzed in aqueous solution to [RuCl(OH2)3(CQ)]2 [Cl]2, which is probably the active species. This compound binds to hematin in solution and inhibits aggregation to β-hematin at pH ∼ 5 to a slightly lower extent than chloroquine diphosphate; more importantly, the heme aggregation inhibition activity of complex 1 is significantly higher than that of CQ when measured at the interface of n-octanol-aqueous acetate buffer mixtures under acidic conditions modeling the food vacuole of the parasite. Partition coefficient measurements confirmed that complex 1 is considerably more lipophilic than CQ in n-octanol-water mixtures at pH ∼ 5. This suggests that the principal target of complex 1 is the heme aggregation process, which has recently been reported to be fast and spontaneous at or near water-lipid interfaces. The enhanced antimalarial activity of complex 1 is thus probably due to a higher effective concentration of the drug at or near the interface compared with that of CQ, which accumulates strongly in the aqueous regions of the vacuole under those conditions. Furthermore, the activity of complex 1 against CQ-resistant strains of P. falciparum is probably related to its greater lipophilicity, in line with previous reports indicating a lowered ability of the mutated transmembrane transporter PfCRT to promote the efflux of highly lipophilic drugs. The metal complex also interacts with DNA by intercalation, to a comparable extent and in a similar manner to uncomplexed CQ and therefore DNA binding does not appear to be an important part of the mechanism of antimalarial action in this case. |
| Related Links | http://dx.doi.org/10.1007/s00775-008-0356-9 |
| Ending Page | 712 |
| Page Count | 10 |
| Starting Page | 703 |
| File Format | |
| ISSN | 09498257 |
| e-ISSN | 14321327 |
| Journal | Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry |
| Issue Number | 5 |
| Volume Number | 13 |
| Language | English |
| Publisher Date | 2008-06-01 |
| Access Restriction | Open |
| Subject Keyword | Inorganic Chemistry Biochemistry Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Biochemistry Inorganic Chemistry |
