Browsing by Author "Espinosa-Bustos, Christian"

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    2,3-Diketopiperazine as potential scaffold to develop new anti-Chagasic agents
    (2023) Osorio-Nieto, Urbano; Salas, Cristian O.; Mendez-Alvarez, Domingo; Rivera, Gildardo; Moreno-Rodriguez, Adriana; Perez-Cervera, Yobana; Castillo-Real, Lizet Monserrat; Espinosa-Bustos, Christian
    Continuing our program to develop compounds with potential activity against Trypanosoma cruzi, in this work we have designed and synthesized and evaluated in vitro on the trypomastigote form a new series of 2,3-diketopiperazines derivatives. By means of a two-step sequence, where one of them was a catalytic and selective C(sp(3))-H-bond reaction, nine final compounds (5a-i) were obtained. Most of these 2,3-diketopiperazines were highly active against the trypomastigote strain NINOA (LC50 < 100 mu M) compared to the reference drugs benznidazole (Bzn) and nifurtimox (Nfx). Likewise, compounds 5c and 5h showed high potency against the trypomastigote strain A1 (LC50 = 25.2 and 40.49 mu M, respectively), with 5c being four to five times more active than the reference drugs. In addition, the cytotoxicity of these compounds was determined in the murine macrophage J774 cell line, presenting in most cases, higher selectivity rates compared to Bzn and Nfx. In silico studies suggested that these 2,3-diketopiperazine derivatives could be inhibitors of the Fe-SOD enzyme at the cytosolic and mitochondrial level. Finally, these compounds would also have good oral bioavailability according to theoretical predictions.
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    A convenient and simple synthesis of N-arylpirrolopyrimidines using boronic acids and promoted by copper (II) acetate
    (2017) Espinosa-Bustos, Christian; Villegas, Alondra; Salas, Cristian O.
    A convenient and simple synthesis of novel N-arylated 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine using several aryl boronic acids and copper (II) acetate is described. The yields obtained for all derivatives are in the range of 45-70 % and this synthetic approach is extensible to other heterocycles such as 1H-indazoles.
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    Electrochemical oxidation of chlorpromazine, characterisation of products by mass spectroscopy and determination in pharmaceutical samples
    (2023) Martinez-Rojas, Francisco; Espinosa-Bustos, Christian; Ramirez, Galo; Armijo, Francisco
    The electrochemical behaviour of chlorpromazine (CPZ) at different pH values was studied using a fluorinedoped tin oxide (FTO) electrode. Cyclic voltammetry (CV), square-wave voltammetry (SWV), electrochemical impedance spectroscopy (EIS), and constant-potential electrolysis were used to elucidate the electrooxidation mechanism of CPZ on the FTO electrode, whereas chronoamperometry was used to determine CPZ in pharmaceutical and water samples. In addition, using mass spectrometry (MS), it was determined that the main oxidation product was the metabolite chlorpromazine sulfoxide (CPZ-SO). When electrolysis was performed at 1.45 V and pH 2, two metabolites were detected by MS, and a competitive mechanism was proposed wherein CPZ-SO was obtained simultaneously. Linear analytical curves were obtained between 2 x 10-6 and 100 x 10-6 mol L-1, and the detection limit was determined to be 0.26 x 10-6 mol L-1. The developed electroanalytical method thereby presents an appropriate sensitivity and stability that renders it suitable for use in the quality control and routine quantification of pharmaceutical formulations and samples containing environmentally relevant concentrations.
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    Hepatoprotective species from the Chilean medicinal flora: Junellia spathulata (Verbenaceae)
    (2021) Bridi, Raquel; von Poser, Gilsane Lino; Gomez, Miguel; Andia, Marcelo E.; Esteban Oyarzun, Juan; Nunenz, Paula; Vasquez Arias, Ariadsna Jael; Espinosa-Bustos, Christian
    Ethnopharmacological relevance: Chilean population relies on medicinal plants for treating a wide range of illnesses, especially those of the gastrointestinal system. Junellia spathulata (Gillies & Hook.) Moldenke var. spathulata (Verbenaceae), called as "verbena-azul-de-cordilleira", is a medicinal plant native to Argentina and Chile traditionally used for treating digestive disorders. Although the species of the genus ar e important as therapeutic resources for the Andean population, the plants are ver y scarcely studied.
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    New Inhibitors of Bcr-Abl Based on 2,6,9-Trisubstituted Purine Scaffold Elicit Cytotoxicity in Chronic Myeloid Leukemia-Derived Cell Lines Sensitive and Resistant to TKIs
    (2024) Delgado, Thalía; Veselá, Denisa; Dostálová, Hana; Krystof, Vladimir; Vojáčková, Veronika; Jorda, Radek; Castro-Alvarez, Alejandro; Bertrand, Jean Luc; Rivera, Gildardo; Faúndez, M.; Strnad, Miroslav; Espinosa-Bustos, Christian; Salas, Cristian
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    New Smoothened ligands based on the purine scaffold as potential agents for treating pancreatic cancer
    (2024) Espinosa-Bustos, Christian; Bertrand, Jeanluc; Villegas-Menares, Alondra; Guerrero, Simon; Di Marcotullio, Lucia; Navacci, Shirin; Schulte, Gunnar; Kozielewicz, Pawel; Bloch, Nicolas; Villela, Valentina; Paulino, Margot; Kogan, Marcelo J.; Cantero, Jorge; Salas, Cristian O.
    Aberrant activation of the Hedgehog (Hh) signalling pathway has been associated with the development and progression of pancreatic cancer. For this reason, blockade of Hh pathway by inhibitors targeting the G proteincoupled receptor Smoothened (SMO) has been considered as a therapeutic target for the treatment of this cancer. In our previous work, we obtained a new SMO ligand based on a purine scaffold (compound I), which showed interesting antitumor activity in several cancer cell lines. In this work, we report the design and synthesis of 17 new purine derivatives, some of which showed high cytotoxic effect on Mia-PaCa-2 (Hh-dependent pancreatic cancer cell lines) and low toxicity on non-neoplastic HEK-293 cells compared with gemcitabine, such as 8f, 8g and 8h (IC50 = 4.56, 4.11 and 3.08 mu M, respectively). Two of these purines also showed their ability to bind to SMO through NanoBRET assays (pKi = 5.17 for 8f and 5.01 for 8h), with higher affinities to compound I (pKi = 1.51). In addition, docking studies provided insight the purine substitution pattern is related to the affinity on SMO. Finally, studies of Hh inhibition for selected purines, using a transcriptional functional assay based on luciferase activity in NIH3T3 Shh-Light II cells, demonstrated that 8g reduced GLI activity with a IC50 = 6.4 mu M as well as diminished the expression of Hh target genes in two specific Hh-dependent cell models, Med1 cells and Ptch1- /- mouse embryonic fibroblasts. Therefore, our results provide a platform for the design of SMO ligands that could be potential selective cytotoxic agents for the treatment of pancreatic cancer.
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    Photoaged polystyrene nanoplastics exposure results in reproductive toxicity due to oxidative damage in Caenorhabditis elegans
    (2024) Leon, Rocio Errazuriz; Salcedo, Vicente Andre Araya; Miguel, Francisco Javier Novoa San; Tardio, Cynthia Rosa Andrea Llanquinao; Briceno, Adolfo Andres Tobar; Fouilloux, Stefano Francesco Cherubini; Barbosa, Marcela de Matos; Barros, Cesar Antonio Saldias; Waldman, Walter Ruggeri; Espinosa-Bustos, Christian; Carneiro, Maria Fernanda Hornos
    The increase of plastic production together with the incipient reuse/recycling system has resulted in massive discards into the environment. This has facilitated the formation of micro- and nanoplastics (MNPs) which poses major risk for environmental health. Although some studies have investigated the effects of pristine MNPs on reproductive health, the effects of weathered MNPs have been poorly investigated. Here we show in Caenorhabditis elegans that exposure to photoaged polystyrene nanoplastics (PSNP-UV) results in worse reproductive performance than pristine PSNP (i.e., embryonic/larval lethality plus a decrease in the brood size, accompanied by a high number of unfertilized eggs), besides it affects size and locomotion behavior. Those effects were potentially generated by reactive products formed during UV -irradiation, since we found higher levels of reactive oxygen species and increased expression of GST-4 in worms exposed to PSNP-UV. Those results are supported by physical -chemical characterization analyses which indicate significant formation of oxidative degradation products from PSNP under UV -C irradiation. Our study also demonstrates that PSNP accumulate predominantly in the gastrointestinal tract of C. elegans (with no accumulation in the gonads), being completely eliminated at 96 h post -exposure. We complemented the toxicological analysis of PSNP/PSNP-UV by showing that the activation of the stress response via DAF-16 is dependent of the nanoplastics accumulation. Our data suggest that exposure to the wild PSNP, i.e., polystyrene nanoplastics more similar to those actually found in the environment, results in more important reprotoxic effects. This is associated with the presence of degradation products formed during UV -C irradiation and their interaction with biological targets.
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    Solvent-Free Synthesis of New Quinoline Derivatives via Eaton's Reagent Catalysed Friedlander Synthesis
    (2022) Satheeshkumar, Rajendran; Prasad, Karnam Jayarampillai Rajendra; Wang Wen-Long; Espinosa-Bustos, Christian; Salas, Cristian O.
    An interest for the development of new 2-acetyl/propanoyl quinolines via Friedlander synthesis is one of the most studied synthetic approaches. Herein we report the use of a freshly prepared Eaton's reagent (phosphorus pentoxide in methanesulfonic acid) as catalyst without solvents to obtain quinoline derivatives. Eleven 2-acetylquinolines were synthesized in high yields (85-96%) from symmetrical 1,2-diketone, butan-2,3-dione with o-aminoarylketones in the presence of Eaton's reagent. Subsequently, a novel regioselective solvent free reaction is reported for synthesis of o-aminoarylketones with unsymmetrical 1,2-diketone, pentan-2,3-dione, to yield different 2-propanoylquinolines. Eaton's reagent performs a unique way of this reaction as a powerful desiccant, condensing, cyclizing and dehydrating agent. Among these advantages of Eaton's reagent was found as an inexpensive and easily accessible catalyst for the Friedlander synthesis.