DSpace Angular :: Browsing by Author "Benites, Julio"

Browsing by Author "Benites, Julio"

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An in vitro comparative study with furyl-1,4-quinones endowed with anticancer activities
(2011) Benites, Julio; Valderrama, Jaime A.; Taper, Henryk; Calderon, Pedro Buc
We describe the biological activity of some furylbenzo- and naphthoquinones (furylquinones) on hepatocarcinoma cells and healthy rat liver slices. The effects of furylquinones on cancer cells (Transplantable Liver Tumor, TLT) were assessed by measuring cell death (membrane cell lysis); intracellular contents of ATP and GSH and the activity of caspase-3 were used to determine the type of cell death. Most of the furylquinones tested (at a concentration of 25 mu g/ml) induced caspase-independent cell death but compound 4 had no cytotoxic effects. The levels of both ATP and GSH were severely affected by quinones 1, 2 and 5, while no effect was observed with compound 4. These cytotoxic properties of quinones are associated with physico-chemical properties as shown by the LUMO energies and lipophilicity. Interestingly, no cytotoxic effects of furylquinones were detected when the in vitro model of precision-cut liver slices (PCLS) was used. Indeed, although CYP2E1 activity was slightly affected, ATP and GSH levels as well as protein synthesis were not modified by furylquinones. Paracetamol, a well-known hepatotoxicant, reduced these parameters by more than 80% compared to control conditions. Taking into account the considerable incidence of adverse-effects induced by most current anticancer drugs, the selective cytotoxicity shown by compounds 1, 2 and 5, in particular that of 1, represents a safety factor that encourages the further development of these quinones as new drugs in cancer therapy.
ANTIPROLIFERATIVE ACTIVITY OF NEW 6-BROMINE DERIVATIVES OF 7-ANILINO-1-ARYLISOQUINOLINEQUINONES
(2016) Andrea Ibacache, Juana; Valderrama, Jaime A.; Arancibia, Veronica; Theoduloz, Cristina; Muccioli, Giulio G.; Benites, Julio
A variety of 6-bromine-containing 7-anilino-1-arylisoquinolinequinones 2a-g were synthesized to evaluate their half-wave potentials and in vitro antiproliferative activity on gastric and leukemia cancer cell lines. The new compounds displayed significant IC50 values in the range: 1.31 to 11.04 mu M. The structure activity relationship analysis of the new series suggest that the antiproliferative activity is dependent, in part, on the push-pull electronic effects of the nitrogen and bromine substituents inserted into the redox fragment of the 1-arylisoquinolinequinone scaffold. Linear regression analysis provided satisfactory relationships between the log IC50 and ClogP values for the AGS gastric cancer cell line.
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
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
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.
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
Discovery of New 2-Phenylamino-3-acyl-1,4-naphthoquinones as Inhibitors of Cancer Cells Proliferation: Searching for Intra-Cellular Targets Playing a Role in Cancer Cells Survival
(2023) Benites, Julio; Valderrama, Jaime A.; Contreras, Alvaro; Enriquez, Cinthya; Pino-Rios, Ricardo; Yanez, Osvaldo; Calderon, Pedro Buc
A series of 2-phenylamino-3-acyl-1,4-naphtoquinones were evaluated regarding their in vitro antiproliferative activities using DU-145, MCF-7 and T24 cancer cells. Such activities were discussed in terms of molecular descriptors such as half-wave potentials, hydrophobicity and molar refractivity. Compounds 4 and 11 displayed the highest antiproliferative activity against the three cancer cells and were therefore further investigated. The in silico prediction of drug likeness, using pkCSM and SwissADME explorer online, shows that compound 11 is a suitable lead molecule to be developed. Moreover, the expressions of key genes were studied in DU-145 cancer cells. They include genes involved in apoptosis (Bcl-2), tumor metabolism regulation (mTOR), redox homeostasis (GSR), cell cycle regulation (CDC25A), cell cycle progression (TP53), epigenetic (HDAC4), cell-cell communication (CCN2) and inflammatory pathways (TNF). Compound 11 displays an interesting profile because among these genes, mTOR was significantly less expressed as compared to control conditions. Molecular docking shows that compound 11 has good affinity with mTOR, unraveling a potential inhibitory effect on this protein. Due to the key role of mTOR on tumor metabolism, we suggest that impaired DU-145 cells proliferation by compound 11 is caused by a reduced mTOR expression (less mTOR protein) and inhibitory activity on mTOR protein.
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
Impact of the Potential Antitumor Agent 2-(4-Hydroxyphenyl) Amino-1,4-Naphthoquinone (Q7) on Vasomotion Is Mediated by the Vascular Endothelium, But Not Vascular Smooth Muscle Cell Metabolism
(2021) Palacios, Javier; Benites, Julio; Owen, Gareth, I; Morales, Pablo; Chiong, Mario; Nwokocha, Chukwuemeka R.; Paredes, Adrian; Cifuentes, Fredi
Vasomotion is defined as rhythmic oscillations in arterial diameter that regulate the blood flow and blood pressure. Because antitumor treatment may impair vascular functions and increase the blood pressure, we sought to evaluate whether a new naphthoquinone derivative, postulated as an antitumor agent, manifests adverse effects on vascular function. In this article, we evaluated the toxicity of 2-(4-hydroxyphenyl) amino-1,4-naphthoquinone (Q7) and its effects on vascular vasomotion in 3 models of vascular structure: endothelial cells, aortic ring, and smooth muscle cells. Although showing nontoxic effects, Q7 inhibited the formation of capillary-like structures of the EA.hy926 endothelial cell line grown on Matrigel. In exvivo experiments with aortic rings precontracted with phenylephrine (PE, 10(-6) M), Q7 (10(-5) M) significantly (P < 0.05) reduced vascular rhythmic contractions induced by the acetylcholine (ACh; 10(-7)-10(-5) M), whereas sodium nitroprusside (a nitric oxide donor; 10(-8) M) recovered the vasomotion. Furthermore, Q7 (10(-5) M) did not decrease KCl-induced vascular rhythmic contractions in the aortic rings precontracted with BaCl2 (a nonselective K+ channel blocker; 10(-3) M). Vascular smooth muscle cells (A7r5) preincubated with Q7 (10(-5) M) for 3 hours also demonstrated a reduced glucose uptake. However, the Adenosine Triphosphate content was unaffected, suggesting that the rapid reduction in vasomotion observed in vascular reactivity experiments did not involve cellular metabolism but may be due to faster mechanisms involving endothelial nitric oxide and K+ channels leading to oscillations in intracellular Ca2+. In summary, the naphthoquinone derivative Q7 presents low cytotoxicity yet may alter the endothelial cell response and vasomotion in the absence of changes in smooth muscle cell metabolism.
Mild and rapid method for the generation of o-quinone methide intermediates.: Synthesis of puupehedione analogues
(2006) Barrero, Alejandro F.; del Moral, Jose F. Quilez; Herrador, M. Mar; Arteaga, Pilar; Cortes, Manuel; Benites, Julio; Rosellon, Antonio
A route to simpler analogues to bioactive puupehedione derivatives involving a hetero Diels-Alder cycloaddition of a o-quinone methide is described. These intermediate species are generated via fluoride-induced desilylation of silyl derivatives of o-hydroxybenzyl iodides. Remarkable short reaction times and very mild experimental conditions are the main features of this method. (c) 2006 Elsevier Ltd. All rights reserved.
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.
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.
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.
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.
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
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
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.
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.
Substituted 3-acyl-2-phenylamino-1,4-naphthoquinones intercalate into DNA and cause genotoxicity through the increased generation of reactive oxygen species culminating in cell death
(2014) Farias, Mirelle Sifroni; Pich, Claus Troeger; Kviecinski, Maicon Roberto; Falcao Bucker, Nadia Cristina; Felipe, Karina Bettega; Da Silva, Fabiana Ourique; Fisher Guenther, Tania Mara; Correia, Joao Francisco; Rios, David; Benites, Julio; Valderrama, Jaime A.; Buc Calderon, Pedro; Pedrosa, Rozangela Curi
Naphthoquinones interact with biological systems by generating reactive oxygen species (ROS) that can damage cancer cells. The cytotoxicity and the antitumor activity of 3-acyl-2-phenylamino-1,4-naphthoquinones (DPB1-DPB9) were evaluated in the MCF7 human breast cancer cell line and in male Ehrlich tumor-bearing Balb/c mice. DPB4 was the most cytotoxic derivative against MCF7 cells (EC50 15 mu M) and DPB6 was the least cytotoxic one (EC50 56 mu M). The 1,4-naphthoquinone derivatives were able to cause DNA damage and promote DNA fragmentation as shown by the plasmid DNA cleavage assay (FII form). In addition, 1,4-naphthoquinone derivatives possibly interacted with DNA as intercalating agents, which was demonstrated by the changes caused in the fluorescence of the DNA-ethidium bromide complexes. Cell death of MCF7 cells induced by 3-acyl-2-phenylamino-1,4-naphthoquinones was mostly due to apoptosis. The DNA fragmentation and subsequent apoptosis may be correlated to the redox potential of the 1,4-naphthoquinone derivatives that, once present in the cell nucleus, led to the increased generation of ROS. Finally, certain 1,4-naphthoquinone derivatives and particularly DPB4 significantly inhibited the growth of Ehrlich ascites tumors in mice (73%).
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.

Browsing by Author "Benites, Julio"

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