Browsing by Author "Estevez, Juan C."

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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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    Gold-Facilitated '6-Exo-dig' Intramolecular Cyclization of 2-[(2-Nitrophenyl)ethynyl]phenylacetic Acids: General Access to 5H-Benzo[b]carbazole-6,11-diones
    (2009) Salas Sánchez, Cristián Osvaldo; Reboredo, Francisco J.; Estevez, Juan C.; Tapia Apati, Ricardo; Estevez, Ramon J.
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    Studies on the Michael addition of naphthoquinones to sugar nitro olefins: first synthesis of polyhydroxylated hexahydro-11H-benzo[a]carbazole-5,6-diones and hexahydro-11bH-benzo[b]carbazole-6,11-diones
    (PERGAMON-ELSEVIER SCIENCE LTD, 2012) Otero, Jose M.; Barcia, Jose C.; Salas, Cristian O.; Thomas, Pablo; Estevez, Juan C.; Estevez, Ramon J.
    A strategy for the synthesis of the novel (6bR,7R,8S,9S,10S,10aR)-8-(benzyloxy)-7,9,10-trihydroxy-6b,7,8,9,10,10a-hexahydro-11H-benzo[a]carbazole-5,6-dione is reported. The key steps were the Michael addition of 2-hydroxy-1,4-naphthoquinone to 1-nitrocyclohexene or 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-nitro-alpha-D-xylo-hex-5-enefuranose and the diastereoselective intramolecular Henry reaction of 3-O-benzyl-5,6-dideoxy-S-C-(3'-hydroxy-1',4'-naphthoquinon-2'-yl)-1,2-O-isopropylidene-6-nitro-alpha-D-glucofuranose to give the key (1S,25,35,4R,5R,6R)-3-(benzyloxy)-1,2,4-trihydroxy-5-(3'-hydroxy-1',4'-naphthoquinon-2'-yl)-6-nitrocyclohexane. When 2-hydroxy-1,4-naphthoquinone was replaced by (1,4-dimethoxynaphthalen-2-yl)lithium, the novel (1R,2S,35,4R,4aS,11bS)-2-(benzyloxy)-1,3,4-trihydroxy-1,2,3,4,4a,5-hexahydro-11bH-benzo[b]carbazole-6,11-dione was obtained. (C) 2011 Elsevier Ltd. All rights reserved.