Primaquine can mediate hydroxyl radical generation by Trypanosomacruzi extracts

Augusto, Ohára; Alves, Maria Júlia M.; Colli, Walter; Filardi, Leny S.; Brener, Z.

doi:10.1016/0006-291x(86)91031-4

Cited by 13 publications

(5 citation statements)

References 11 publications

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“…Previous studies of the phenotypes of PTR1 and DHFR-TS knockouts and overexpressors (Bello, et al 1994, Cruz, et al 1991, Nare, et al 1997a) indicated that unconjugated pteridines have uncharacterized functions in Leishmania , one of which we now assign as oxidant resistance. Interestingly, amplification of the H region in response to primaquine, a compound thought to act via the production of ROS (Augusto, et al 1986), led to the suggestion that one of the H region proteins and possibly PTR1 were implicated in oxidant resistance (Bello, et al 1994, Ellenberger and Beverley 1989). …”

Section: Discussionmentioning

confidence: 99%

PTR1-dependent synthesis of tetrahydrobiopterin contributes to oxidant susceptibility in the trypanosomatid protozoan parasite Leishmania major

et al. 2009

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Leishmania must survive oxidative stress, but lack many classical antioxidant enzymes and rely heavily on trypanothione-dependent pathways. We used forward genetic screens to recover loci mediating oxidant resistance via overexpression in Leishmania major, which identified pteridine reductase 1 (PTR1). Comparisons of isogenic lines showed ptr1 -null mutants were 18-fold more sensitive to H 2 O 2 than PTR1-overproducing lines, and significant 3-5 fold differences were seen with a broad panel of oxidant-inducing agents. The toxicities of simple nitric oxide generators and other drug classes (except antifolates) were unaffected by PTR1 levels. H 2 O 2 susceptibility could be modulated by exogenous biopterin but not folate, in a PTR1-but not dihydrofolate reductasedependent manner, implicating H 4 B metabolism specifically. Neither H 2 O 2 consumption, nor the level of intracellular oxidative stress, was affected by PTR1 levels. Coupled with the fact that reduced pteridines are at least 100-fold less abundant than cellular thiols), these data argue strongly that reduced pteridines act through a mechanism other than scavenging. The ability of unconjugated pteridines to counter oxidative stress has implications to infectivity and response to chemotherapy. Since the intracellular pteridine levels of Leishmania can be readily manipulated, these organisms offer a powerful setting for the dissection of pteridine-dependent oxidant susceptibility in higher eukaryotes.

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Section: Discussionmentioning

confidence: 99%

PTR1-dependent synthesis of tetrahydrobiopterin contributes to oxidant susceptibility in the trypanosomatid protozoan parasite Leishmania major

et al. 2009

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“…Hydroxymethylnitrofurazone (NFOH - 91 ) was first reported by Chung and coworkers (2003), as an intermediate of the Mannich reaction, in one of the mechanisms ( Bundgaard and Johansen, 1980a ) used to synthesize mutual prodrugs with primaquine (PQ – 92 ) and nitrofurazone (NF – 93 ) that are potentially active drugs used in Chagas disease. Currently, PQ ( 92 ) is an antimalarial drug and its antichagasic activity ( Kondrashin et al, 2014 ) is due to active metabolites able to cause oxidative stress in the parasite, leading to T. cruzi death ( Augusto et al, 1986 ). However, PQ ( 92 ) activity was not sustainable, probably due to the action of trypanothione reductase, a key enzyme in the parasite defense mechanism, acting as an antioxidant ( Cazzulo et al, 2001 ).…”

Section: Hydroxymethylnitrofurazone: a History Of Well-succeeded Hydr...mentioning

confidence: 99%

Drug/Lead Compound Hydroxymethylation as a Simple Approach to Enhance Pharmacodynamic and Pharmacokinetic Properties

et al. 2022

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Hydroxymethylation is a simple chemical reaction, in which the introduction of the hydroxymethyl group can lead to physical–chemical property changes and offer several therapeutic advantages, contributing to the improved biological activity of drugs. There are many examples in the literature of the pharmaceutical, pharmacokinetic, and pharmacodynamic benefits, which the hydroxymethyl group can confer to drugs, prodrugs, drug metabolites, and other therapeutic compounds. It is worth noting that this group can enhance the drug’s interaction with the active site, and it can be employed as an intermediary in synthesizing other therapeutic agents. In addition, the hydroxymethyl derivative can result in more active compounds than the parent drug as well as increase the water solubility of poorly soluble drugs. Taking this into consideration, this review aims to discuss different applications of hydroxymethyl derived from biological agents and its influence on the pharmacological effects of drugs, prodrugs, active metabolites, and compounds of natural origin. Finally, we report a successful compound synthesized by our research group and used for the treatment of neglected diseases, which is created from the hydroxymethylation of its parent drug.

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“…8,9 Although the mechanism is not completely understood, it has been proposed that PQ acts as a trypanocidal agent through redox cycling with generation of active oxygen species. 10 The use of PQ, however, is limited by its toxic effects, among them hemolytic anemia, particularly in patients who are deficient in glucose-6-phosphate dehydrogenase.…”

Section: Introductionmentioning

confidence: 99%

“…Boc-Lys(Cl-Z)-Arg(Tos)-PQ (9) was obtained through the coupling of 8 with Boc-Lys(Cl-Z)-OH. HF treatment of 9 yielded Lys-Arg-PQ (10). The coupling of the derivative 8 to Boc-Phe-OH gave Boc-Phe-Arg(Tos)-PQ (11), which was fully deprotected using HF to yield the dipeptide derivative Phe-Arg-PQ.HF (12).…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and in Vitro Evaluation of Potential Antichagasic Dipeptide Prodrugs of Primaquine

Chin

Goncalves

Colli

et al. 1997

Journal of Pharmaceutical Sciences

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American trypanosomiasis (Chagas' disease) is an endemic parasitic disease afflicting more than 20 million people in Latin America. Currently, therapy is unsatisfactory and only two drugs are available. Primaquine, an antimalarial drug, has trypanocidal activity. Dipeptide derivatives of primaquine, Phe-Arg-PQ, Lys-Arg-PQ, and Phe-Ala-PQ, were synthesized. The choice of the peptides was based on the primary specificity of cruzipain, the major cysteine proteinase from T cruzi. The prodrugs obtained were tested on the LLC-MK2 cell culture infected with trypomastigotes forms of T. cruzi. Phe-Arg-PQ, Lys-Arg-PQ, and Phe-Ala-PQ were active in all stages.

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Primaquine can mediate hydroxyl radical generation by Trypanosomacruzi extracts

Cited by 13 publications

References 11 publications

PTR1-dependent synthesis of tetrahydrobiopterin contributes to oxidant susceptibility in the trypanosomatid protozoan parasite Leishmania major

PTR1-dependent synthesis of tetrahydrobiopterin contributes to oxidant susceptibility in the trypanosomatid protozoan parasite Leishmania major

Drug/Lead Compound Hydroxymethylation as a Simple Approach to Enhance Pharmacodynamic and Pharmacokinetic Properties

Synthesis and in Vitro Evaluation of Potential Antichagasic Dipeptide Prodrugs of Primaquine

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