Bisphosphonate metal complexes as selective inhibitors of Trypanosoma cruzi farnesyl diphosphate synthase
| Autor: | Francesco Caruso, Hugo Cerecetto, Dinorah Gambino, Roberto Docampo, Leena Malayil, Alvaro W. Mombrú, Mercedes González, Miriam Rossi, Bruno Demoro, Diego Benítez, Lucía Otero, Melina Galizzi, Ricardo Faccio |
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| Rok vydání: | 2012 |
| Předmět: |
Stereochemistry
Antiparasitic medicine.drug_class Trypanosoma cruzi Crystal structure Inorganic Chemistry Metal chemistry.chemical_compound Inhibitory Concentration 50 Farnesyl diphosphate synthase Chlorocebus aethiops medicine Organometallic Compounds Animals Humans Enzyme Inhibitors Amastigote Vero Cells Cell Proliferation chemistry.chemical_classification biology Diphosphonates Geranyltranstransferase Serum Albumin Bovine biology.organism_classification Phosphonate Enzyme chemistry visual_art biology.protein visual_art.visual_art_medium |
| Zdroj: | Dalton transactions (2003. Print) 41 (2012): 6468–6476. doi:10.1039/C2DT12179D info:cnr-pdr/source/autori:Bruno Demoro, Francesco Caruso, Miriam Rossi, Diego Benítez, Mercedes González, Hugo Cerecetto, Melina Galizzi, Leena Malayil, Roberto Docampo, Ricardo Faccio, Álvaro W. Mombrú, Dinorah Gambino, Lucía Otero/titolo:Bisphosphonate metal complexes as selective inhibitors of Trypanosoma cruzi farnesyl diphosphate synthase./doi:10.1039%2FC2DT12179D/rivista:Dalton transactions (2003. Print)/anno:2012/pagina_da:6468/pagina_a:6476/intervallo_pagine:6468–6476/volume:41 |
| ISSN: | 1477-9234 |
| DOI: | 10.1039/C2DT12179D |
| Popis: | In the search for a pharmacological answer to treat Chagas disease, eight metal complexes with two bioactive bisphosphonates, alendronate (Ale) and pamidronate (Pam), were described. Complexes of the formula [M(2)(II)(Ale)(4)(H(2)O)(2)]·2H(2)O, with M = Cu, Co, Mn, Ni, and ([CuPam]·H(2)O)(n) as well as [M(II)(Pam)(2)(H(2)O)(2)]·3H(2)O, with M = Co, Mn and Ni, were synthesized and fully characterized. Crystal structure of [Cu(2)(II)(Ale)(4)(H(2)O)(2)]·2H(2)O, [Co(II)(Pam)(2)(H(2)O)(2)] and [Ni(II)(Pam)(2)(H(2)O)(2)] were solved by X-ray single crystal diffraction methods and the structures of [M(2)(II)(Ale)(4)(H(2)O)(2)]·2H(2)O complexes M = Co, Mn and Ni were studied by X-ray powder diffraction methods. All obtained complexes were active against the amastigote form of Trypanosoma cruzi (T. cruzi), etiological agent of Chagas disease. Most of them were more active than the corresponding free ligands showing no toxicity for mammalian cells. The main mechanism of the antiparasitic action of bisphosphonates, inhibition of parasitic farnesyl diphosphate synthase (TcFPPS), remains in the obtained metal complexes and an increase in the inhibiting enzyme levels was observed upon coordination. Observed enzymatic inhibition was selective for TcFPPS as the metal complexes showed no or little inhibition of human FPPS. Additionally, metal complexation might improve the bioavailability of the complexes through the hindrance of the phosphonate group's ionization at physiological pH and, eventually, through the ability of plasma proteins to work as complex transporters. |
| Databáze: | OpenAIRE |
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