LQB-118, an orally active pterocarpanquinone, induces selective oxidative stress and apoptosis in Leishmania amazonensis

Ribeiro, Grazielle Alves; Cunha-Júnior, Edézio Ferreira; Pinheiro, Roberta Olmo; Da-Silva, Silvia A. G.; Canto‐Cavalheiro, Marilene M.; Silva, Alcides José Monteiro da; Costa, Paulo R.R.; Netto, Chaquip D.; Melo, Rossana C. N.; Almeida-Amaral, Elmo Eduardo; Torres-Santos, Eduardo Caio

doi:10.1093/jac/dks498

Cited by 65 publications

(49 citation statements)

References 33 publications

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“…We also have contributed in the understanding of the cell death mechanism that is induced by LQB-118. We reported that LQB-118 induces ROS production in L. amazonensis promastigotes a few minutes after incubation and it is sustained after 24 h, suggesting that this event is one of the parasite death triggers (13). Increased ROS levels were also found in L. braziliensis promastigotes treated with LQB-118 (12).…”

Section: Discussionmentioning

confidence: 82%

“…The pterocarpanquinone LQB-118, the lead compound from this class, has antiprotozoal and anti-leukemic cell line activities, even in cells with an multidrug resistance phenotype (8)(9)(10). We have also demonstrated that LQB-118 is effective in treating experimental cutaneous leishmaniasis via oral delivery (11,12), and the death of Leishmania amazonensis parasites involved oxidative stress with hallmarks of apoptosis (13). These results suggest that LQB-118 is a promising lead compound and should be further investigated.…”

mentioning

confidence: 70%

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Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

Cunha-Júnior

Martins

Canto‐Cavalheiro

et al. 2016

Antimicrob Agents Chemother

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e Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is the second major cause of death by parasites, after malaria. The arsenal of drugs against leishmaniasis is small, and each has a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. Our group has focused on studying new drug candidates as alternatives to current treatments. The pterocarpanquinone LQB-118 was designed and synthesized based on molecular hybridization, and it exhibited antiprotozoal and antileukemic cell line activities. Our previous work demonstrated that LQB-118 was an effective treatment for experimental cutaneous leishmaniasis. In this study, we observed that treatment with 10 mg/kg of body weight/day LQB-118 orally inhibited the development of hepatosplenomegaly with a 99% reduction in parasite load. An in vivo toxicological analysis showed no change in the clinical, biochemical, or hematological parameters. Histologically, all of the analyzed organs were normal, with the exception of the liver, where focal points of necrosis with leukocytic infiltration were observed at treatment doses 5 times higher than the therapeutic dose; however, these changes were not accompanied by an increase in transaminases. Our findings indicate that LQB-118 is effective at treating different clinical forms of leishmaniasis and presents no relevant signs of toxicity at therapeutic doses; thus, this framework is demonstrated suitable for developing promising drug candidates for the oral treatment of leishmaniasis.

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 70%

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

Cunha-Júnior

Martins

Canto‐Cavalheiro

et al. 2016

Antimicrob Agents Chemother

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“…Intracellular ATP levels are susceptible to alterations when there is mitochondrial damage, such as changes in the mitochondrial membrane potential and an increase in the levels of reactive oxygen species (51,54). Promastigotes treated with LSPN331 showed a significant decrease in intracellular ATP levels in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

Kaplum

Cogo

Sangi

et al. 2016

Antimicrob Agents Chemother

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Leishmaniasis is endemic in 98 countries and territories worldwide. The therapies available for leishmaniasis have serious side effects, thus prompting the search for new therapies. The present study investigated the antileishmanial activities of 2,3-diarylsubstituted quinoxaline derivatives against Leishmania amazonensis. The antiproliferative activities of 6,7-dichloro-2,3-diphenylquinoxaline (LSPN329) and 2,3-di-(4-methoxyphenyl)-quinoxaline (LSPN331) against promastigotes and intracellular amastigotes were assessed, and the cytotoxicities of LSPN329 and LSPN331 were determined. Morphological and ultrastructural alterations were examined by electron microscopy, and biochemical alterations, reflected by the mitochondrial membrane potential (⌬⌿m), mitochondrial superoxide anion (O 2 · ؊ ) concentration, the intracellular ATP concentration, cell volume, the level of phosphatidylserine exposure on the cell membrane, cell membrane integrity, and lipid inclusions, were evaluated. In vivo antileishmanial activity was evaluated in a murine cutaneous leishmaniasis model. Compounds LSPN329 and LSPN331 showed significant selectivity for promastigotes and intracellular amastigotes and low cytotoxicity. In promastigotes, ultrastructural alterations were observed, including an increase in lipid inclusions, concentric membranes, and intense mitochondrial swelling, which were associated with hyperpolarization of ⌬⌿m, an increase in the O 2 · ؊ concentration, decreased intracellular ATP levels, and a decrease in cell volume. Phosphatidylserine exposure and DNA fragmentation were not observed. The cellular membrane remained intact after treatment. Thus, the multifactorial response that was responsible for the cellular collapse of promastigotes was based on intense mitochondrial alterations. BALB/c mice treated with LSPN329 or LSPN331 showed a significant decrease in lesion thickness in the infected footpad. Therefore, the antileishmanial activity and mitochondrial mechanism of action of LSPN329 and LSPN331 and the decrease in lesion thickness in vivo brought about by LSPN329 and LSPN331 make them potential candidates for new drug development for the treatment of leishmaniasis.

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“…Apesar do paládio oferecer a vantagem de ser mais versátil e eficiente em reações de aminação, as reações de acoplamento C-N na presença de sais ou óxidos de cobre em estado de oxidação (I) ou (II) são muito empregadas para a síntese de produtos naturais, pois o cobre é bastante econômico CHEPRAKOV, 2004;DEJON et al, 2013;ZHU et al, 2013b (MAIA et al, 2011;DE SÁ BACELAR et al, 2013;RIBEIRO et al, 2013;COSTA et al, 2014;MARTINO et al, 2014).…”

Section: Reações Em "úNico Pote" Catalisadas Por Cobreunclassified

“…O LQB 118 (93) é uma substância classificada como pterocarpanquinona devido a uma hibridação entre um pterocarpano (pertencente à classe dos isoflavonoídes) e o lapachol (RIBEIRO et al, 2013). Em virtude da potente ação anticâncer do LQB 118 (93), foi desenvolvido o LQB 192 (94), denominado azapterocarpanquinona, na qual foi feita uma troca do grupo oxigênio pelo arilsulfonamida, grupo responsável pela ação biológica de muitos fármacos (BOGEN et al, 2010;BASHIR et al, 2011;DE OLIVEIRA et al, 2011;LUO et al, 2011;YANG et al, 2011;MALWAL et al, 2012;ZOUMPOULAKIS et al, 2012) MALWAL et al, 2012NEITZEL et al, 2011;ZOUMPOULAKIS et al, 2012;AL-DOSARI et al, 2013;GHORAB et al, 2010GHORAB et al, , 2015CARTA et al, 2015;REDDY et al, 2015).…”

Section: Reações Em "úNico Pote" Catalisadas Por Cobreunclassified

Síntese De 11a-N-Arilsulfonil-Tetrahidro-5h-Benzo[a]carbazóis Com Ação Antitumoral

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LQB-118, an orally active pterocarpanquinone, induces selective oxidative stress and apoptosis in Leishmania amazonensis

Abstract: Our results suggest that LQB-118 selectively induces ROS-triggered and mitochondria-dependent apoptosis in this parasite.

Cited by 65 publications

References 33 publications

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

Síntese De 11a-N-Arilsulfonil-Tetrahidro-5h-Benzo[a]carbazóis Com Ação Antitumoral

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