Potent naphthoquinones against antimony-sensitive and -resistant Leishmania parasites: Synthesis of novel α- and nor-α-lapachone-based 1,2,3-triazoles by copper-catalyzed azide–alkyne cycloaddition

Guimarães, Tiago T.; Pinto, Maria do Carmo F. R.; Lanza, Juliane S.; Melo, Maria Norma; Monte-Neto, Rubens L.; Melo, Isadora M.M. de; Diogo, Emilay B. T.; Ferreira, Vı́tor F.; Câmara, Celso A.; Valença, Wagner O.; Oliveira, Ronaldo N. de; Frézard, Frédéric; Júnior, Eufrânio N. da Silva

doi:10.1016/j.ejmech.2013.02.038

Cited by 94 publications

(29 citation statements)

References 48 publications

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“…The intermediate compound 4 was obtained by the reaction of 3-ethynylaniline and the bromo derivative 3 . As previously reported [40], 4-azide-α-lapachone ( 5 ) was easily synthesized from the reaction of 3 with sodium azide in dichloromethane. The reaction of 5 and phenyl propargyl selenide affords selenium-containing α-lapachone 1,2,3-triazole 7 .…”

Section: Resultsmentioning

confidence: 99%

“…Since the synthesis of arylamino substituted lapachones and azidoquinones are well established in our group [25,40,42], compounds 13 and 14 were prepared as shown in Scheme 3. Following click methodology, compounds 13 and 14 were reacted with selenium-containing azide and alkyne, respectively, to furnish the naphthoquinones 15 and 16 in 70% and 80% yield, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…The previously published azido derivatives 5 , 9 , 14 , 20 , 25 , 39 , 46 were prepared as described in the literature [40-42,46-48]. Compound 28 (1.0 mmol) was prepared from 27 in the presence of sodium azide (120 mg, 1.85 mmol) in 2 mL of dimethylformamide (DMF).…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and antitumor activity of selenium-containing quinone-based triazoles possessing two redox centres, and their mechanistic insights

Cruz

Silvers

Jardim

et al. 2016

European Journal of Medicinal Chemistry

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Selenium-containing quinone-based 1,2,3-triazoles were synthesized using click chemistry, the copper catalyzed azide-alkyne 1,3-dipolar cycloaddition, and evaluated against six types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), PC3 (human prostate cells), SF295 (human glioblastoma cells), MDA-MB-435 (melanoma cells) and OVCAR-8 (human ovarian carcinoma cells). Some compounds showed IC50 values < 0.3 μM. The cytotoxic potential of the quinones evaluated was also assayed using non-tumor cells, exemplified by peripheral blood mononuclear (PBMC), V79 and L929 cells. Mechanistic role for NAD(P)H:Quinone Oxidoreductase 1 (NQO1) was also elucidated. These compounds could provide promising new lead derivatives for more potent anticancer drug development and delivery, and represent one of the most active classes of lapachones reported.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Synthesis and antitumor activity of selenium-containing quinone-based triazoles possessing two redox centres, and their mechanistic insights

Cruz

Silvers

Jardim

et al. 2016

European Journal of Medicinal Chemistry

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“…Natural plant-derived quinones and their derivatives may exert multifactorial effects upon distinct targets on antiparasitic chemotherapy (Pinto and Castro, 2009, Salas et al., 2008, Belorgey et al., 2013). Naphtoquinones such as β–lapachone are natural products isolated from different higher plant families and shown to present antimalarial (Carvalho et al., 1988, De Andrade-Neto et al., 2004, Pérez-Sacau et al., 2005), giardicidal (Corrêa et al., 2009), leishmanicidal (Guimarães et al., 2013) and trypanocidal activity against T. brucei (De Pahn et al., 1988) and Trypanosoma cruzi (Boveris et al., 1978, Docampo et al., 1978, Goijman and Stoppani, 1985, Pinto et al., 1997, Pinto et al., 2000, Menna-Barreto et al., 2005, Menna-Barreto et al., 2007, Menna-Barreto et al., 2009a, 2014). Furthermore, lapachone derivatives/analogues may display enhanced antiparasitic activity upon T. cruzi (Pinto et al., 1997; Ferreira et al., 2011, Diogo et al., 2013).…”

Section: Introductionmentioning

confidence: 99%

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

Anjos

Alves

Goncalves

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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Natural products comprise valuable sources for new antiparasitic drugs. Here we tested the effects of a novel β–lapachone derivative on Trypanosoma cruzi parasite survival and proliferation and used microscopy and cytometry techniques to approach the mechanism(s) underlying parasite death. The selectivity index determination indicate that the compound trypanocidal activity was over ten-fold more cytotoxic to epimastigotes than to macrophages or splenocytes. Scanning electron microscopy analysis revealed that the R72 β–lapachone derivative affected the T. cruzi morphology and surface topography. General plasma membrane waving and blebbing particularly on the cytostome region were observed in the R72-treated parasites. Transmission electron microscopy observations confirmed the surface damage at the cytostome opening vicinity. We also observed ultrastructural evidence of the autophagic mechanism termed macroautophagy. Some of the autophagosomes involved large portions of the parasite cytoplasm and their fusion/confluence may lead to necrotic parasite death. The remarkably enhanced frequency of autophagy triggering was confirmed by quantitating monodansylcadaverine labeling. Some cells displayed evidence of chromatin pycnosis and nuclear fragmentation were detected. This latter phenomenon was also indicated by DAPI staining of R72-treated cells. The apoptotis induction was suggested to take place in circa one-third of the parasites assessed by annexin V labeling measured by flow cytometry. TUNEL staining corroborated the apoptosis induction. Propidium iodide labeling indicate that at least 10% of the R72-treated parasites suffered necrosis within 24 h. The present data indicate that the β–lapachone derivative R72 selectively triggers T. cruzi cell death, involving both apoptosis and autophagy-induced necrosis.

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“…The methodology for the synthesis of 4 and 5 is well described in the literature. 31,32 Cyclic lapachones were obtained by insertion of bromine atoms and nucleophilic substitution with sodium azide to afford the respective clickable analogues 4 and 5.…”

Section: Resultsmentioning

confidence: 99%

On the synthesis of quinone-based BODIPY hybrids: New insights on antitumor activity and mechanism of action in cancer cells

Gontijo

Freitas

Emery

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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Fluorescent quinone-based BODIPY hybrids were synthesised and characterised by NMR analysis and mass spectrometry. We measured their cytotoxic activity against cancer and normal cell lines, performed mechanistic studies by lipid peroxidation and determination of reduced (GSH) and oxidized (GSSG) glutathione, and imaged their subcellular localisation by confocal microscopy. Cell imaging experiments indicated that nor-β-lapachone-based BODIPY derivatives might preferentially localise in the lysosomes of cancer cells. These results assert the potential of hybrid quinone-BODIPY derivatives as promising prototypes in the search of new potent lapachone antitumor drugs.

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Potent naphthoquinones against antimony-sensitive and -resistant Leishmania parasites: Synthesis of novel α- and nor-α-lapachone-based 1,2,3-triazoles by copper-catalyzed azide–alkyne cycloaddition

Cited by 94 publications

References 48 publications

Synthesis and antitumor activity of selenium-containing quinone-based triazoles possessing two redox centres, and their mechanistic insights

Synthesis and antitumor activity of selenium-containing quinone-based triazoles possessing two redox centres, and their mechanistic insights

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

On the synthesis of quinone-based BODIPY hybrids: New insights on antitumor activity and mechanism of action in cancer cells

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