000130068 001__ 130068 000130068 005__ 20240122171020.0 000130068 0247_ $$2doi$$a10.1021/acs.joc.0c00276 000130068 0248_ $$2sideral$$a117610 000130068 037__ $$aART-2020-117610 000130068 041__ $$aeng 000130068 100__ $$0(orcid)0000-0002-6924-7488$$aCastan, A. 000130068 245__ $$aDebenzylative Cycloetherification as a Synthetic Tool in the Diastereoselective Synthesis of 3, 6-Disubstituted Hexahydro-2H-furo[3, 2-b]pyrroles, PDE1 Enzyme Inhibitors with an Antiproliferative Effect on Melanoma Cells 000130068 260__ $$c2020 000130068 5060_ $$aAccess copy available to the general public$$fUnrestricted 000130068 5203_ $$aTwo series of novel chiral hexahydro-2H-furo[3, 2-b]pyrroles, 4-(7, 8-dimethoxyquinazolin-4-yl) series A and 4-(6, 7-dimethoxyquinazolin-4-yl) series B, were synthesized in enantiomerically pure form and evaluated for their inhibitory effects on phosphodiesterase 1 (PDE1) and phosphodiesterase 4 (PDE4) as well as for their inhibitory activity on cell proliferation in A375 melanoma and 3T3 fibroblast cells in vitro. Key steps of synthesis were (i) diastereoselective nucleophilic addition of vinylmagnesium bromide to N-allylimine derived from conveniently protected D-glyceraldehyde, (ii) ring-closing metathesis, (iii) debenzylative cycloetherification, and (iv) aromatic nucleophilic substitution. Some of the obtained compounds were proven to be active as inhibitors of PDE1 isoforms, with IC50 values in the high nanomolar/low micromolar concentration range, and showed antiproliferative activity on A375 melanoma cells. 000130068 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E45-17R 000130068 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/ 000130068 590__ $$a4.354$$b2020 000130068 591__ $$aCHEMISTRY, ORGANIC$$b12 / 57 = 0.211$$c2020$$dQ1$$eT1 000130068 592__ $$a1.2$$b2020 000130068 593__ $$aOrganic Chemistry$$c2020$$dQ1 000130068 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion 000130068 700__ $$0(orcid)0000-0002-5554-3040$$aBadorrey, R.$$uUniversidad de Zaragoza 000130068 700__ $$aDiez, J.A. 000130068 700__ $$aChristoffersen, C.T. 000130068 700__ $$aRasmussen, L.K. 000130068 700__ $$aKehler, J. 000130068 700__ $$0(orcid)0000-0002-0833-9717$$aKohler, R. 000130068 700__ $$0(orcid)0000-0002-4972-7476$$aGalvez, J.A.$$uUniversidad de Zaragoza 000130068 700__ $$0(orcid)0000-0001-9033-8459$$aDiaz-de-Villegas, M.D. 000130068 7102_ $$12013$$2765$$aUniversidad de Zaragoza$$bDpto. Química Orgánica$$cÁrea Química Orgánica 000130068 773__ $$g85, 9 (2020), 5941-5951$$pJ. org. chem.$$tJournal of Organic Chemistry$$x0022-3263 000130068 8564_ $$s769181$$uhttps://zaguan.unizar.es/record/130068/files/texto_completo.pdf$$yPostprint 000130068 8564_ $$s1004700$$uhttps://zaguan.unizar.es/record/130068/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint 000130068 909CO $$ooai:zaguan.unizar.es:130068$$particulos$$pdriver 000130068 951__ $$a2024-01-22-15:24:49 000130068 980__ $$aARTICLE