Although quinones have been the subject of great interest as possible antimalarial agents, the mechanism of their antimalarial activity is poorly understood. Flavoenzyme electrontransferase-catalyzed redox cycling of quinones, and their inhibition of the antioxidant flavoenzyme glutathione reductase (GR, EC 22.214.171.124) have been proposed as possible mechanisms. Here, we have examined the activity of a number of quinones, including the novel antitumor agent RH1, against the malaria parasite Plasmodium falciparum strain FcB1 in vitro, their single-electron reduction rates by P. falciparum ferredoxin:NADP+ reductase (PfFNR, EC 126.96.36.199), and their ability to inhibit P. falciparum GR. The multiparameter statistical analysis of our data implies, that the antiplasmodial activity of fully-substituted quinones (n = 15) is relatively independent from their one-electron reduction potential (E71). The presence of aziridinyl groups in quinone ring increased their antiplasmodial activity. Since aziridinyl-substituted quinones do not possess enhanced redox cycling activity towards PfFNR, we propose that they could act as as DNA-alkylating agents after their net two-electron reduction into aziridinyl-hydroquinones. We found that under the partial anaerobiosis, i.e., at the oxygen concentration below 40-50 μM, this reaction may be carried out by single-electron transferring flavoenzymes present in P. falciparum, like PfFNR. Another parameter increasing the antiplasmodial activity of fully-substituted quinones is an increase in their potency as P. falciparum GR inhibitors, which was revealed using multiparameter regression analysis. To our knowledge, this is the first quantitative demonstration of a link between the antiplasmodial activity of compounds and GR inhibition.
Antiplasmodial activity of quinones : Roles of aziridinyl substituents and the inhibition of Plasmodium falciparum glutathione reductase / P. Grellier, A. Maroziene, H. Nivinskas, J. Šarlauskas, A. Aliverti, N. Čenas. - In: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS. - ISSN 0003-9861. - 494:1(2010 Feb 01), pp. 32-39.
|Titolo:||Antiplasmodial activity of quinones : Roles of aziridinyl substituents and the inhibition of Plasmodium falciparum glutathione reductase|
ALIVERTI, ALESSANDRO (Penultimo)
|Parole Chiave:||aziridinylbenzoquinones; bioreductive activation; ferredoxin:nadp+ reductase; glutathione reductase; inhibition of; medzq; plasmodium falciparum; quinones; rh1; animals; aziridines; enzyme inhibitors; erythrocytes; glutathione reductase; humans; kinetics; plasmodium falciparum; quinones; regression analysis; biophysics; biochemistry; molecular biology|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
Settore BIO/14 - Farmacologia
|Data di pubblicazione:||1-feb-2010|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.abb.2009.11.012|
|Appare nelle tipologie:||01 - Articolo su periodico|