000151626 001__ 151626
000151626 005__ 20250319155217.0
000151626 0247_ $$2doi$$a10.1021/acs.joc.1c01308
000151626 0248_ $$2sideral$$a126162
000151626 037__ $$aART-2021-126162
000151626 041__ $$aeng
000151626 100__ $$aClemente F.
000151626 245__ $$aPiperidine Azasugars Bearing Lipophilic Chains: Stereoselective Synthesis and Biological Activity as Inhibitors of Glucocerebrosidase (GCase)
000151626 260__ $$c2021
000151626 5060_ $$aAccess copy available to the general public$$fUnrestricted
000151626 5203_ $$aWe report a straightforward synthetic strategy for the preparation of trihydroxypiperidine azasugars decorated with lipophilic chains at both the nitrogen and the adjacent carbon as potential inhibitors of the lysosomal enzyme glucocerebrosidase (GCase), which is involved in Gaucher disease. The procedure relies on the preparation of C-erythrosyl N-alkylated nitrones 10 through reaction of aldehyde 8 and primary amines 13 followed by oxidation of the imines formed in situ with the methyltrioxorhenium catalyst and urea hydrogen peroxide. The addition of octylMgBr to nitrone 10e provided access to both epimeric hydroxylamines 21 and 22 with opposite configuration at the newly created stereocenter in a stereodivergent and completely stereoselective way, depending on the absence or presence of BF3·Et2O. Final reductive amination and acetonide deprotection provided compounds 14 and 15 from low-cost d-mannose in remarkable 43 and 32% overall yields, respectively, over eight steps. The C-2 R-configured bis-alkylated trihydroxypiperidine 15 was the best ligand for GCase (IC50 = 15 µM), in agreement with MD simulations that allowed us to identify the chair conformation corresponding to the best binding affinity.
000151626 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E34-20R$$9info:eu-repo/grantAgreement/ES/MINECO/CTQ2016-77270-R$$9info:eu-repo/grantAgreement/ES/MINECO/PID2019-104090RB-100
000151626 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000151626 590__ $$a4.198$$b2021
000151626 591__ $$aCHEMISTRY, ORGANIC$$b12 / 56 = 0.214$$c2021$$dQ1$$eT1
000151626 592__ $$a0.983$$b2021
000151626 593__ $$aOrganic Chemistry$$c2021$$dQ1
000151626 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000151626 700__ $$aMatassini C.
000151626 700__ $$aGiachetti S.
000151626 700__ $$aGoti A.
000151626 700__ $$aMorrone A.
000151626 700__ $$aMartínez-Bailén M.
000151626 700__ $$aOrta S.
000151626 700__ $$0(orcid)0000-0002-2202-3460$$aMerino P.$$uUniversidad de Zaragoza
000151626 700__ $$aCardona F.
000151626 7102_ $$12013$$2765$$aUniversidad de Zaragoza$$bDpto. Química Orgánica$$cÁrea Química Orgánica
000151626 773__ $$g86, 18 (2021), 12745-12761$$pJ. org. chem.$$tJournal of Organic Chemistry$$x0022-3263
000151626 8564_ $$s4802833$$uhttps://zaguan.unizar.es/record/151626/files/texto_completo.pdf$$yVersión publicada
000151626 8564_ $$s2662994$$uhttps://zaguan.unizar.es/record/151626/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000151626 909CO $$ooai:zaguan.unizar.es:151626$$particulos$$pdriver
000151626 951__ $$a2025-03-19-14:19:32
000151626 980__ $$aARTICLE