ABSTRACT
Electrophilic fluorination of an exocyclic methoxymethylene enol ether derived from N-tert-butyloxycarbonyl-1,5-dideoxy-1,5-imino-3,4-O-isopropylidene-D-erythro-pent-2-ulose (11) provided the 5-fluoro derivative of the powerful ß-galactosidase inhibitor 4-epi-isofagomine (8). This structural alteration, in combination with N-alkylation, led to considerably improved α-galactosidase selectivity. New compounds may serve as leads en route to new pharmacological chaperones for Fabry's disease.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Galactosidases/antagonists & inhibitors , Imino Pyranoses/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fabry Disease/drug therapy , Fabry Disease/enzymology , Gangliosidosis, GM1/drug therapy , Gangliosidosis, GM1/enzymology , Halogenation , Humans , Imino Pyranoses/chemistry , Imino Pyranoses/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of previously unknown bridgehead-functionalized bicyclo[2.2.2]octasilanes, Me3Si-Si8Me12-X, X-Si8Me12-X, and X-Si8Me12-Y [X, Y = -SiMe n Ph3-n (n = 1, 2) (2, 3, 10), -SiMe2Fc (Fc = ferrocenyl) (4, 11, 13, 14), -COR (R = Me, tBu) (6, 7, 12), COOMe (8), COOH (9)], have been prepared by the reaction of the silanides Me3Si-Si8Me12-K+ or K+-Si8Me12-K+ with proper electrophiles and fully characterized. The molecular structures of 2, 3, 4, 6, 8, 9, 10, and 13 as determined by single-crystal X-ray diffraction analysis exhibit a slightly twisted structure of the bicyclooctasilane cage. Endocyclic bond lengths, bond angles, and dihedral angles are not influenced considerably by the substituents attached to the bridgehead silicon atoms. Due to σ(SiSi)/π(aryl) conjugation, a 20-30 nm bathochromic shift of the longest wavelength UV absorption band relative to Me3Si-Si8Me12-SiMe3 (1) is evident in the UV absorption spectra of the phenyl and ferrocenyl derivatives. Otherwise, UV absorption data do not support the assumption of aryl/aryl or aryl/C=O interaction via the σ(SiSi) bicyclooctasilane framework.
