Browsing by Author "Benites, Julio"

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    Antiproliferative effects of phenylaminonaphthoquinones are increased by ascorbate and associated with the appearance of a senescent phenotype in human bladder cancer cells
    (2013) Felipe, K. B.; Benites, Julio; Glorieux, Ch.; Sid, Brice; Valenzuela Valderrama, Manuel; Kviecinski, Maicon; Pedrosa, Rozangela C.; Valderrama Guerrero, Jaime Adolfo; Levêque, Philippe; Gallez, Bernard; Verrax, J.; Calderón, P. Buc
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    Binding of dihydroxynaphthyl aryl ketones to tubulin colchicine site inhibits microtubule assembly
    (2015) Gutierrez, Eunices; Benites, Julio; Valderrama Guerrero, Jaime Adolfo; Calderon, Pedro Buc; Verrax, Julien; Nova, Esteban; Villanelo, Felipe; Maturana, Daniel; Escobar, Cristian; Lagos, Rosalba; Monasterio, Octavio
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    Biological evaluation of donor-acceptor aminonaphthoquinones as antitumor agents
    (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2010) Benites, Julio; Valderrama, Jaime A.; Bettega, Karina; Pedrosa, Rozangela Curi; Buc Calderon, Pedro; Verrax, Julien
    Several members of the phenylamino-1,4-naphthoquinone series were prepared in order to investigate structure-activity relationships (SAR) and to explore the antitumor effects associated with this scaffold. The cytotoxic effects of the aminoquinones (EC50) against a panel of cancer cell lines (MCF7, DU145 and T24 cells) and healthy fibroblasts (BALB/3T3) were assessed in vitro using the MTT reduction assay 48 h after drug exposure. SAR analysis of the aminonaphthoquinone series showed that insertion of a chlorine atom in the acceptor quinone nucleus and/or insertion of a methyl group at the nitrogen atom of the donor phenylamino group induced significant changes in cytotoxic activity. Quinones 7 and 9, which exhibited the highest selective indexes (5.73 and 6.29, respectively), were further characterized using the following assays: Colony formation, caspase-3 activity, and ATP content. The results showed that aminoquinone 7 strongly influenced ATP levels and impaired the proliferative capacity of T24 cells without activating caspase-3. (C) 2010 Elsevier Masson SAS. All rights reserved.
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    Conversion of (+)-confertifolin into 11,12-bisnordriman-9-one and (+)-8 alpha H,9 alpha H-11,12-diacetoxydrimane
    (2001) Benites, Julio; Preite, Marcelo Daniel; Cortés Marescotti, Manuel
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    Eco-friendly synthesis and antiproliferative evaluation of some oxygen substituted diaryl ketones
    (2013) Arenas, Paola; Peña, Andrés; Ríos, David; Benites, Julio; Muccioli, Giulio G.; Calderón, Pedro Buc; Valderrama Guerrero, Jaime Adolfo
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    New cyclic acetals related to Ambergris and their olfactory evaluation
    (SAGE PUBLICATIONS LTD, 2006) Benites, Julio; Armstrong, Veronica; Cortes, Manuel
    Hemisyntheses of cyclic acetals (11-18) were performed using (-)-polygodial and (+)-confertifolin as chiral starting materials. The acetals obtained were evaluated for their odoriferous properties.
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    Part 1: Effect of vitamin C on the biological activity of two euryfurylbenzoquinones on TLT, a murine hepatoma cell line
    (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2008) Benites, Julio; Rojo, Leonel; Valderrama, Jaime A.; Taper, Henryk; Calderon, Pedro Buc
    2-Euryfuryl- and 2-euryfuryl-3-nitro-1,4-benzoquinone Q2 and Q3, prepared via oxidative coupling reactions of sesquiterpene euryfuran 1 to 2-nitro-1,4-benzoquinone and 1,4-benzoquinone, were tested for their cytotoxicity towards TLT cells (a murine hepatoma cell line) in the absence and in the presence of vitamin C. Their cytotoxic profile was completely different. In cells incubated with Q2 (from 1 to 50 mu g/ml), cell survival was not modified, both GSH and ATP were depleted to about 50% of control values (at 50 mu g/ml); and caspase-3 was activated in a dose-dependent manner. These effects were observed whatever cells were incubated or not in the presence of vitamin C. In the case of Q3, the cytotoxicity was rather unrelated to its concentration but the association of vitamin C plus the highest Q3 concentration (50 mu g/ml) results in a strong cell death (more than 60%). At such a concentration, a complete lack of caspase-3 activity was observed, probably due to cell lysis. At lower concentrations of Q3 (1 and 10 mu g/ml), caspase-3 activity was lower than that observed in the absence of vitamin C or even under control conditions. Both GSH and ATP were kept fairly constant as compared to control values but in the presence of vitamin C and Q3, at 50 mu g/ml, a decrease in their amounts was observed. (C) 2007 Elsevier Masson SAS. All rights reserved.
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    Part 2: Influence of 2-Euryfuryl-1,4-naphthoquinone and Its peri-Hydroxy Derivatives on Both Cell Death and Metabolism of TLT Cells, a Murine Hepatoma Cell Line. Modulation of Cytotoxicity by Vitamin C
    (PHARMACEUTICAL SOC JAPAN, 2009) Benites, Julio; Adolfo Valderrama, Jaime; Taper, Henryk; Calderon, Pedro Buc
    2-Euryfuryl-1,4-naphthoquinone C-1 and its 5- and 5,8-hydroxy derivatives C-2 and C-3, were tested for their cytotoxicity towards transplantable liver tumor (TLT) cells (a murine hepatoma cell line) in the absence and in the presence of vitamin C. Cell death, caspase-3 activity and two metabolic end-points, namely the intracellular content of ATP and glutathione (GSH), were employed to evaluate their cytotoxicity. In a range of concentration from 0 to 10 mu g/ml C-1 and C-3 were non toxic against TLT cells, while compound C-2 killed about 50% of cells by necrosis. Interestingly, the presence of vitamin C did not enhance the cytolysis of C-2, but its addition exacerbated the effects of the three compounds on both ATP and GSH contents, the two metabolic end points selected in our study. Our assumption is that the electron donor effect of the peri-hydroxyl substituents on euryfurylnaphthoquinones and the hydrogen bond between the peri-hydroxy and quinone carbonyl groups influence the electron-acceptor capability of the quinone nucleus and thus modifies the electron transfer from ascorbate to the electroactive quinone nucleus. The combination of euryfurylnaphthoquinones with vitamin C may he of potential clinical interest, because cancer cells accumulate vitamin C, they are sensitive to an oxidant insult and they depend on glycolysis (ATP formation) for their survival.
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    Redox-Active Quinones and Ascorbate: An Innovative Cancer Therapy That Exploits the Vulnerability of Cancer Cells to Oxidative Stress
    (BENTHAM SCIENCE PUBL LTD, 2011) Verrax, Julien; Beck, Raphael; Dejeans, Nicolas; Glorieux, Christophe; Sid, Brice; Pedrosa, Rozangela C.; Benites, Julio; Vasquez, David; Valderrama, Jaime A.; Buc Calderon, Pedro
    Cancer cells are particularly vulnerable to treatments impairing redox homeostasis. Reactive oxygen species (ROS) can indeed play an important role in the initiation and progression of cancer, and advanced stage tumors frequently exhibit high basal levels of ROS that stimulate cell proliferation and promote genetic instability. In addition, an inverse correlation between histological grade and antioxidant enzyme activities is frequently observed in human tumors, further supporting the existence of a redox dysregulation in cancer cells. This biochemical property can be exploited by using redox-modulating compounds, which represent an interesting approach to induce cancer cell death. Thus, we have developed a new strategy based on the use of pharmacologic concentrations of ascorbate and redox-active quinones. Ascorbate-driven quinone redox cycling leads to ROS formation and provokes an oxidative stress that preferentially kills cancer cells and spares healthy tissues. Cancer cell death occurs through necrosis and the underlying mechanism implies an energetic impairment (ATP depletion) that is likely due to glycolysis inhibition. Additional mechanisms that participate to cell death include calcium equilibrium impairment and oxidative cleavage of protein chaperone Hsp90. Given the low systemic toxicity of ascorbate and the impairment of crucial survival pathways when associated with redox-active quinones, these combinations could represent an original approach that could be combined to standard cancer therapy.
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    Regiospecific Michael reaction of (+)-euryfuran with activated 1,4-benzoquinones
    (2000) Valderrama Guerrero, Jaime Adolfo; Cortés Cortés, Manuel Enrique; Pessoa Mahana, Carlos David; Preite, Marcelo Daniel; Benites, Julio
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    Studies on quinones. Part 35 : Access to antiprotozoal active euryfurylquinones and hydroquinones
    (2002) Valderrama Guerrero, Jaime Adolfo; Benites, Julio; Cortés Cortés, Manuel Enrique; Pessoa Mahana, Carlos David; Prina, Eric; Fournet, Alain
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    Studies on quinones. Part 42: Synthesis of furylquinone and hydroquinones with antiproliferative activity against human tumor cell lines
    (PERGAMON-ELSEVIER SCIENCE LTD, 2008) Benites, Julio; Valderrama, Jaime A.; Rivera, Felipe; Rojo, Leonel; Campos, Nair; Pedro, Madalena; Jose Nascimento, Maria Saeo
    The preparation of furyl-1,4-quinone and hydroquinones by reaction of 2-furaldehyde N,N-dimethylhydrazone with benzo- and naphthoquinones is reported. Access to furylnaphthoquinones from unactivated quinones requires acid-induced conditions, however oxidative coupling reactions of activated quinones proceed under neutral conditions. The in vitro cytotoxic activity of the prepared compounds against a panel of three human cancer cell lines has been studied. Most of the furyl-1,4-quinones exhibited good antiproliferative activity (GI(50) = 6.5-33.5 mu m) against the MCF-7, NCI-H460, and SF-268 (CNS cancer) cell lines chosen for testing. (C) 2007 Elsevier Ltd. All rights reserved.
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    Studies on quinones. Part 47. Synthesis of novel phenylaminophenanthridinequinones as potential antitumor agents
    (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2011) Valderrama, Jaime A.; Ibacache, Andrea; Rodriguez, Jaime A.; Theoduloz, Cristina; Benites, Julio
    In our search for potential anticancer agents, a series of 8- and 9-phenylamino-3,4-tetrahydro-phenanthridine-1,7,10(2H)-triones with substituent variations at 6-, 8- and 9-positions were prepared using a highly efficient sequence involving: a) solar photoacylation reactions of benzoquinone with arylaldehydes, b) one-pot procedure for the synthesis of 3,4-dihydrophenanthridine-1,7,10(2H)-trione intermediates from acylhydroquinones and c) highly regiocontrolled acid-induced amination reaction of phenanthridinequinones with phenylamines. The members of this series were in vitro evaluated using the KIT colorimetric method against one normal cell line and three human cancer cell lines. The SAR analysis indicates that the location of nitrogen substituents on the quinone nucleus, the presence of methyl, phenyl, furyl and thienyl groups at the 6-position and the aromatization of the angular cyclo-aliphatic ring of the phenylamino-3,4-tetrahydrophenanthridine-1,7,10(2H)-trione pharmacophore play key roles in the antitumor activity. (C) 2011 Elsevier Masson SAS. All rights reserved.
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    Synthesis and Antitumor Evaluation of 6-Aryl-substituted benzo[j]phenanthridine- and Benzo[g]pyrimido[4,5-c]isoquinolinequinones
    (MDPI, 2012) Iribarra, Jennyfer; Vasquez, David; Theoduloz, Cristina; Benites, Julio; Rios, David; Valderrama, Jaime A.
    A variety of novel 6-arylsubstituted benzo[j]phenanthridine-and benzo[g]pyrimido[4,5-c]isoquinolinequinones were synthesized from 1,4-naphthoquinone, aryl-aldehydes and enaminones via a two-step synthetic approach. The cytotoxic activity of the aminoquinone derivatives was evaluated in vitro against one normal cell line (MRC-5 lung fibroblasts) and three human cancer cell lines (AGS human gastric adenocarcinoma; SK-MES-1 human lung cancer cells, and J82 human bladder carcinoma) in 72-h drug exposure assays using the MTT colorimetric method. Structure-activity relationships within the series of angular quinones reveal that the insertion of pyrrol-2-yl and furan-2-yl groups at the 6-position is more significant for the increase of the potency and selectivity index of the pharmacophores.
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    Synthesis and Cytotoxic Activity on Human Cancer Cells of Novel Isoquinolinequinone-Amino Acid Derivatives
    (2016) Valderrama Guerrero, Jaime Adolfo; Delgado Chang, Virginia; Sepúlveda, Sandra; Benites, Julio; Theoduloz, Cristina; Buc Calderón, Pedro; Muccioli, Giulio G.
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    Synthesis and in vitro antiproliferative evaluation of 3-acyl-2-arylamino-1,4-naphthoquinones
    (2014) Ríos, David; Benites, Julio; Torrejón, Felipe; Theoduloz, Cristina; Valderrama Guerrero, Jaime Adolfo
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    Synthesis, half-wave potentials and antiproliferative activity of 1-Aryl-substituted aminoisoquinolinequinones
    (2014) Ibacache, Juana Andrea; Delgado Chang, Virginia; Benites, Julio; Theoduloz, Cristina; Arancibia Moya, Verónica; Muccioli, Giulio G.; Valderrama Guerrero, Jaime Adolfo
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    The solar-chemical photo-Friedel-Crafts heteroacylation of 1,4-quinones
    (PERGAMON-ELSEVIER SCIENCE LTD, 2011) Benites, Julio; Rios, David; Diaz, Pilar; Valderrama, Jaime A.
    Photochemical reactions between 1,4-benzo- and 1,4-naphthoquinone and several heteroaromatic carbaldehydes were investigated under solar irradiation conditions. These reactions gave the corresponding heteroacylated hydroquinones in the range 71%-92% yield. (C) 2010 Elsevier Ltd. All rights reserved.