Browsing by Author "Salas, Cristian O."

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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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    Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists
    (2023) Prieto-Diaz, Ruben; Gonzalez-Gomez, Manuel; Fojo-Carballo, Hugo; Azuaje, Jhonny; El Maatougui, Abdelaziz; Majellaro, Maria; Loza, Maria, I; Brea, Jose; Fernandez-Duenas, Victor; Paleo, M. Rita; Diaz-Holguin, Alejandro; Garcia-Pinel, Beatriz; Mallo-Abreu, Ana; Estevez, Juan C.; Andujar-Arias, Antonio; Garcia-Mera, Xerardo; Gomez-Tourino, Iria; Ciruela, Francisco; Salas, Cristian O.; Gutierrez-de-Teran, Hugo; Sotelo, Eddy
    The modulation of the A2B adenosine receptor is a promising strategy in cancer (immuno) therapy, with A2BAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di-and mono-)halogenation at positions 7 and/or 8 on both A2BAR affinity and pharmacokinetic properties of a collection of A2BAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent A2BAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel A2BAR ligands exhibited remarkable affinity (Ki < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells.
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    In vitro and In vivo Biological Activity of Two Aryloxy-naphthoquinones in Mice Infected with Trypanosoma cruzi Strains
    (2024) Vazquez, Karina; Moreno-Rodriguez, Adriana; Dominguez-Diaz, Luis R.; Bertrand, Jeanluc; Salas, Cristian O.; Rivera, Gildardo; Cervera, Yobana Perez; Bocanegra-Garcia, Virgilio
    Background: Chagas disease, a condition caused by Trypanosoma cruzi, is an endemic disease in Latin American countries that affects approximately eight million people worldwide. It is a continuing public health problem. As nifurtimox and benznidazole are the two pharmacological treatments currently used to treat it, the present research proposes new therapeutic alternatives. Previous studies conducted on naphthoquinone derivatives have found interesting trypanocidal effects on epimastigotes, with the molecules 2-phenoxy-1,4-naphthoquinone (IC50= 50 nM and SI < 250) and 2-(3-nitrophenoxy)-naphthalene-1,4-dione (IC50= 20 nM y SI=625) presenting the best biological activity. Method: The present study evaluated the efficacy of in vitro, ex vivo and in vivo models of two aryloxyquinones, 2-phenoxy-1,4-naphthoquinone (1) and 2-(3-nitrophenoxy)-naphthalene-1,4- dione (2), against two Mexican T. cruzi strains in both their epimastigote and blood Trypomastigote stage. Both compounds were evaluated against T. cruzi using a mouse model (CD1) infected with Mexican isolates of T. cruzi, nifurtimox and benznidazole used as control drugs. Finally, the cytotoxicity of the two compounds against the J774.2 mouse macrophage cell line was also determined. Result: The in vitro and in vivo results obtained indicated that both quinones were more active than the reference drugs. Compound 1 presents in vivo activity, showing up to 40% parasite reduction after 8 h of administration, a finding which is 1.25 times more effective than the results obtained using nifurtimox. Conclusion: These are encouraging results for proposing new naphthoquinone derivatives with potential anti-T. cruzi activity
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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.