Pterocarpanquinone LQB-118 Induces Apoptosis in Leishmania (Viannia) braziliensis and Controls Lesions in Infected Hamsters

Abstract

Previous results demonstrate that the hybrid synthetic pterocarpanquinone LQB-118 presents antileishmanial activity against Leishmania amazonensis in a mouse model. The aim of the present study was to use a hamster model to investigate whether LQB-118 presents antileishmanial activity against Leishmania (Viannia) braziliensis, which is the major Leishmania species related to American tegumentary leishmaniasis. The in vitro antileishmanial activity of LQB-118 on L. braziliensis was tested on the promastigote and intracellular amastigote forms. The cell death induced by LQB-118 in the L. braziliensis promastigotes was analyzed using an annexin V-FITC/PI kit, the oxidative stress was evaluated by 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) and the ATP content by luminescence. In situ labeling of DNA fragments by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to investigate apoptosis in the intracellular amastigotes. L. braziliensis-infected hamsters were treated from the seventh day of infection with LQB-118 administered intralesionally (26 µg/kg/day, three times a week) or orally (4,3 mg/kg/day, five times a week) for eight weeks. LQB-118 was active against the L. braziliensis promastigotes and intracellular amastigotes, producing IC50 (50% inhibitory concentration) values of 3,4±0,1 and 7,5±0,8 µM, respectively. LQB-118 induced promastigote phosphatidylserine externalization accompanied by increased reactive oxygen species production and ATP depletion. Intracellular amastigote DNA fragmentation was also observed, without affecting the viability of macrophages. The treatment of L. braziliensis-infected hamsters with LQB-118, either orally or intralesionally, was effective in the control of lesion size, parasite load and increase intradermal reaction to parasite antigen. Taken together, these results show that the antileishmanial effect of LQB-118 extends to L. braziliensis in the hamster model, involves the induction of parasite apoptosis and shows promising therapeutic option by oral or local routes in leishmaniasis.

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

“…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). This oxidative stress is accompanied by loss of the mitochondrial membrane potential in promastigotes.…”

“…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.…”

Preparative chiral separation and absolute configuration of the synthetic pterocarpanquinone LQB‐118

“…Pterocarpanquinones represent a class of synthetic compounds obtained by molecular hybridization of pterocarpan moieties and naphthoquinone groups . These molecules display significant biological activity, including cytotoxicity against human cancer cell lines, inhibition of Toxoplasma gondii growth in vitro, as well as antiinflammatory, antileishmanial, and antineoplastic activities in mice. Among all pterocarpanquinones synthesized, the most promising antileishmanial compound was LQB‐118 (Figure ).…”

“…Among all pterocarpanquinones synthesized, the most promising antileishmanial compound was LQB‐118 (Figure ). This molecule was found to induce apoptosis in Leishmania amazonensis and L. braziliensis besides controlling cutaneous and visceral lesions in infected mice and hamisters . LQB‐118 is currently under preclinical investigation for visceral leishmaniasis .…”

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

“…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).…”