Microwave-assisted solid-phase Dötz benzannulation reaction: a facile synthesis of 2,3-disubstituted-1,4-naphthoquinones

Shanmugasundaram, Muthian; Garcia-Martinez, Israel; Li, Qingyi; Estrada, Abril; Martinez, Nancy E.; Martínez, Luis E.

doi:10.1016/j.tetlet.2005.08.158

Cited by 20 publications

(8 citation statements)

References 32 publications

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“…Two of the compounds (plumbagin = compound 5 and juglone = compound 7 ), which occur naturally in plants as chemicals for defense, were used as internal controls for synthesis of biologically relevant 1, 4-naphthoquinone derivatives. The scheme utilized was unique in that it was the first report to demonstrate the use of the Dötz benzannulation of Fischer carbene complexes with alkynes to form substituted phenols and was the first report to apply these reactions to solid-phase organic synthesis [11]. The goal of the current study was to determine if the products generated by this process possessed the biological activity commonly associated with naphthoquinones.…”

Section: Discussionmentioning

confidence: 99%

“…2, 3-disubstituted naphthoquinones were synthesized on solid support utilizing the Dotz reaction with solid supported Fischer carbine complexes as described [11] . The compounds were analyzed by gas chromatography and ranged from 95–99% purity.…”

Section: Methodsmentioning

confidence: 99%

“…In an effort to create 1, 4-naphthoquinone libraries a novel organic synthesis regime was developed by Shanmugasundaram et. al using microwave-assisted solid-phase Dötz benzannulation reactions [11] . This was the first report to use solid-supported Dötz benzannulation reaction and the subsequent oxidative cleavage process to generate derivatives of this class of quinones.…”

Section: Introductionmentioning

confidence: 99%

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A Small Library of Synthetic Di-Substituted 1, 4-Naphthoquinones Induces ROS-Mediated Cell Death in Murine Fibroblasts

et al. 2014

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Synthesis of compound libraries and their concurrent assessment as selective reagents for probing and modulating biological function continues to be an active area of chemical biology. Microwave-assisted solid-phase Dötz benzannulation reactions have been used to inexpensively synthesize 2, 3-disubstituted-1, 4-naphthoquinone derivatives. Herein, we report the biological testing of a small library of such compounds using a murine fibroblast cell line (L929). Assessment of cellular viability identified three categories of cytotoxic compounds: no toxicity, low/intermediate toxicity and high toxicity. Increased levels of Annexin-V-positive staining and of caspase 3 activity confirmed that low, intermediate, and highly toxic compounds promote cell death. The compounds varied in their ability to induce mitochondrial depolarization and formation of reactive oxygen species (ROS). Both cytotoxic and non-cytotoxic compounds triggered mitochondrial depolarization, while one highly cytotoxic compound did not. In addition, all cytotoxic compounds promoted increased intracellular ROS but the cells were only partially protected from compound-induced apoptosis when in the presence of superoxide dismutase, catalase, or ascorbic acid suggesting utilization of additional pro-death mechanisms. In summary, nine of twelve (75%) 1, 4-naphthoquinone synthetic compounds were cytotoxic. Although the mitochondria did not appear to be a central target for induction of cell death, all of the cytotoxic compounds induced ROS formation. Thus, the data demonstrate that the synthesis regime effectively created cytotoxic compounds highlighting the potential use of the regime and its products for the identification of biologically relevant reagents.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Small Library of Synthetic Di-Substituted 1, 4-Naphthoquinones Induces ROS-Mediated Cell Death in Murine Fibroblasts

et al. 2014

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“…DPNQ was synthesized according to the method previously described (Montoya et al, 2005; Shanmagasundarama et al, 2005). The compound was dissolved in dimethyl sulfoxide (DMSO) and filtered sterile using a 0.22-μm filter (Sigma-Aldrich, St. Louis, Missouri).…”

Section: Methodsmentioning

confidence: 99%

2,3-Diphenyl-1,4-Naphthoquinone: A Potential Chemotherapeutic Agent Against Trypanosoma cruzi

Ramos¹,

Garza²,

Krauth-Siegel³

et al. 2009

Journal of Parasitology

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Chagas disease, caused by Trypanosoma cruzi, is a wide spread infection in Latin America. Currently, only 2 partially effective and highly toxic drugs, i.e., benznidazole and nifurtimox, are available for the treatment of this disease and several efforts are underway in the search for better chemotherapeutic agents. Here, we have determined the trypanocidal activity of 2,3-diphenyl-1,4-naphthoquinone (DPNQ), a novel quinone derivative. In vitro, DPNQ was highly cytotoxic at a low, micromolar concentration (LD 50 = 2.5 μM) against epimastigote, cell-derived trypomastigote, and intracellular amastigote forms of T. cruzi, but not against mammalian cells (LD 50 = 130 μM). In vivo studies on the murine model of Chagas disease revealed that DPNQ-treated animals (3 doses of 10 mg/kg/day) showed a significant delay in parasitemia peak and higher (up to 60%) survival rate 70 days postinfection, when compared to control group (infected, untreated). We also observed a 2-fold decrease in the parasitemia between the control group (infected, untreated) and the treated group (infected, treated). No apparent drug toxicity effects were noticed in the control group (uninfected, treated). In addition, we determined that DPNQ is the first competitive inhibitor of T. cruzi lipoamide dehydrogenase (TcLipDH) thus far described. Our results indicate that DPNQ is a promising chemotherapeutic agent against T. cruzi.Chagas disease, or American trypanosomiasis, caused by the protozoan parasite Trypanosoma cruzi, is one of the most deadly infectious diseases in Latin America (Dias et al., 2002). Recent reports suggest that Chagas disease is a potentially emergent public health concern in the United States due to the increased immigration from Latin American countries where the disease is endemic (Leiby et al., 1999(Leiby et al., , 2002Andrade et al., 2004;Diaz, 2007;Kirchhoff and Pearson, 2007;Young et al., 2007). The only commercially available drug, benznidazole, is effective in the acute or early chronic phase of the infection (de Andrade et al., 1996;Andrade et al., 2004), but shows a much decreased performance among infected individuals during the late chronic phase and can cause severe side effects (Urbina and Docampo, 2003). Recently, the emergence of T. cruzi strains resistant to benznidazole has also been reported (Murta and Romanha, 1998). Moreover, thus far, no vaccine is available to prevent or treat Chagas disease (Minoprio, 2001;Martin and Tarleton, 2004;Garg and Bhatia, 2005). These facts clearly emphasize the urgent need of new therapeutic approaches against this parasite.Quinones and their derivatives possess anticancer, antibacterial, antimalarial, and antifungal activities (Kim et al., 2004;Tasdemir et al., 2006;Verma, 2006;Brondani et al., 2007;Ui et al., 2007). Their biological activity is related to the acceptance of 1 and/or 2 electrons to form § To whom correspondence should be addressed. MATERIALS AND METHODS Reagents and compoundsDPNQ was synthesized according to the method previously described (Montoya e...

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“…Martinez and coworkers reported the first example of a solid-supported D€ otz annulation, by immobilizing the Fisher carbene 88 on a Wang resin. 47 The chromium species was reacted with various alkynes under microwave irradiation to furnish 1,4-naphthoquinones 89 in moderate to good yields, which were successively cleaved from the resin to 90 (Scheme 6.21). While the observed regioselectivity was identical to the corresponding solution-based reactions, exclusive chemoselectivity was observed on the solid support, as no indene, indenone, or cyclobutenone products were observed.…”

Section: Pauson-khand Reactionsmentioning

confidence: 99%

Chemo‐ and Regioselectivity Enhancement in Solid‐Supported Reactions

Young

Deiters

2011

Solid‐Phase Organic Synthesis

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Microwave-assisted solid-phase Dötz benzannulation reaction: a facile synthesis of 2,3-disubstituted-1,4-naphthoquinones

Cited by 20 publications

References 32 publications

A Small Library of Synthetic Di-Substituted 1, 4-Naphthoquinones Induces ROS-Mediated Cell Death in Murine Fibroblasts

A Small Library of Synthetic Di-Substituted 1, 4-Naphthoquinones Induces ROS-Mediated Cell Death in Murine Fibroblasts

2,3-Diphenyl-1,4-Naphthoquinone: A Potential Chemotherapeutic Agent Against Trypanosoma cruzi

Chemo‐ and Regioselectivity Enhancement in Solid‐Supported Reactions

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