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Debenzylative 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

AuthorsCastán, Alejandro; Badorrey, Ramón ; Díez, José A.; Christoffersen, Claus T.; Rasmussen, Lars K.; Kehler, Jan; Köhler, Ralf; Gálvez, José A. ; Díaz de Villegas, María D.
Issue Date2020
PublisherAmerican Chemical Society
CitationJournal of Organic Chemistry 85(9): 5941-5951 (2020)
AbstractTwo 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.
Publisher version (URL)https://doi.org/10.1021/acs.joc.0c00276
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