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Open AccessArticle

Synthesis and Biological Evaluation of Structurally Varied 5′-/6′-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives

1
Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5º Piso, Campo Grande, 1749-016 Lisboa, Portugal
2
Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5º Piso, Campo Grande, 1749-016 Lisboa, Portugal
3
Bereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany
4
Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2019, 12(3), 103; https://doi.org/10.3390/ph12030103
Received: 15 May 2019 / Revised: 25 June 2019 / Accepted: 27 June 2019 / Published: 2 July 2019
(This article belongs to the Special Issue Carbohydrates 2018)
Isonucleosides are rather stable regioisomeric analogs of nucleosides with broad therapeutic potential. We have previously demonstrated the ability of 5′ and 6′-isonucleosides to inhibit the activity of acetylcholinesterase, a major target for Alzheimer’s disease therapy. Continuing with our research on this topic, we report herein on the synthesis and biological evaluation of a variety of novel terminal isonucleosides and theobromine isonucleotide analogs. Xylofuranose-based purine or uracil 5′-isonucleosides and xylofuranos-5′-yl or glucos-6′-yl theobromine derivatives were accessed via Mitsunobu coupling between partially protected xylofuranose or glucofuranose derivatives with a nucleobase using conventional or microwave-assisted heating conditions. Theobromine-containing N-isonucleosidyl sulfonamide and phosphoramidate derivatives were synthesized from isonucleosidyl acetate precursors. The most active compounds in the cholinesterase inhibition assays were a glucopyranose-based theobromine isonucleosidyl acetate, acting as a dual inhibitor of acetylcholinesterase (AChE, Ki = 3.1 µM) and butyrylcholinesterase (BChE, Ki = 5.4 µM), and a 2-O,4-O-bis-xylofuranos-5′-yl uracil derivative, which displayed moderate inhibition of AChE (Ki = 17.5 µM). Docking studies revealed that the active molecules are positioned at the gorge entrance and at the active site of AChE. None of the compounds revealed cytoxic activity to cancer cells as well as to non-malignant mouse fibroblasts. View Full-Text
Keywords: isonucleosides; theobromine; Mitsunobu reaction; cholinesterase inhibitors isonucleosides; theobromine; Mitsunobu reaction; cholinesterase inhibitors
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MDPI and ACS Style

Xavier, N.M.; de Sousa, E.C.; Pereira, M.P.; Loesche, A.; Serbian, I.; Csuk, R.; Oliveira, M.C. Synthesis and Biological Evaluation of Structurally Varied 5′-/6′-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives. Pharmaceuticals 2019, 12, 103. https://doi.org/10.3390/ph12030103

AMA Style

Xavier NM, de Sousa EC, Pereira MP, Loesche A, Serbian I, Csuk R, Oliveira MC. Synthesis and Biological Evaluation of Structurally Varied 5′-/6′-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives. Pharmaceuticals. 2019; 12(3):103. https://doi.org/10.3390/ph12030103

Chicago/Turabian Style

Xavier, Nuno M.; de Sousa, Eduardo C.; Pereira, Margarida P.; Loesche, Anne; Serbian, Immo; Csuk, René; Oliveira, M. C. 2019. "Synthesis and Biological Evaluation of Structurally Varied 5′-/6′-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives" Pharmaceuticals 12, no. 3: 103. https://doi.org/10.3390/ph12030103

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