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

Castan, A. ; Badorrey, R. (Universidad de Zaragoza) ; Diez, J.A. ; Christoffersen, C.T. ; Rasmussen, L.K. ; Kehler, J. ; Kohler, R. ; Galvez, J.A. (Universidad de Zaragoza) ; Diaz-de-Villegas, M.D.

Resumen: Two 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.

Idioma: Inglés

DOI: 10.1021/acs.joc.0c00276

Año: 2020

Publicado en: Journal of Organic Chemistry 85, 9 (2020), 5941-5951
ISSN: 0022-3263

Factor impacto JCR: 4.354 (2020)

Categ. JCR: CHEMISTRY, ORGANIC rank: 12 / 57 = 0.211 (2020) - Q1 - T1

Factor impacto SCIMAGO: 1.2 - Organic Chemistry (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-17R

Tipo y forma: Artículo (PostPrint)

Área (Departamento): Área Química Orgánica (Dpto. Química Orgánica)