RESUMO
Bioisosteric replacement of the 9-azabicyclo[4.2.1]nonane pharmacophoric element of the novel alkaloidal marine toxine pinnamine (5) by the 8-azabicyclo[3.2.1]octane moiety resulted in conformationally restricted analogues 6a and 6c of (-)-ferruginine (4). Key step in the diastereoselective synthesis of these pyranotropanes was the condensation of enantiopure ecgonine methyl ester (9) from the "chiral pool" with the lithium anion of N-tert-butylbutyraldimin and subsequent cyclisation with TFA. The potential nAChR ligands were tested for their in vitro affinity for the (alpha4)2(beta2)3 and the alpha7* nAChR subtypes. Despite obvious structural similarities with the potent alkaloids pinnamine (5) and (-)-ferruginine (4) the pyranotropanes 6a and 6c exhibited distinctly lower nAChR affinities.
Assuntos
Compostos Aza/síntese química , Ciclo-Octanos/síntese química , Receptores Nicotínicos/efeitos dos fármacos , Animais , Compostos Aza/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ciclo-Octanos/farmacologia , Desenho de Fármacos , Técnicas In Vitro , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Conformação Molecular , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Espectrofotometria Infravermelho , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
N omega-Hydroxy-L-arginine (2) was prepared by a multi-stage synthesis; the key step was the addition of hydroxylamine to the protected cyanamide 8. The presence of N-hydroxyguanidines was confirmed, above all, by 15N-NMR investigations. 15N omega-Hydroxy-L-arginine (2) was converted quantitatively to 15NO by NO synthases from macrophages. 15NO was identified by ESR-spectroscopy. These experiments confirm that 15N omega-hydroxy-L-arginine (2) is an intermediate in the biosynthesis of NO from arginine (1) and that the N-hydroxylated N-atom is present in the NO formed.
Assuntos
Arginina/análogos & derivados , Óxido Nítrico/metabolismo , Aminoácido Oxirredutases/metabolismo , Animais , Arginina/síntese química , Arginina/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Camundongos , Óxido Nítrico Sintase , Radioisótopos de NitrogênioRESUMO
Glycosylation of benzyl-2,3,6-trideoxy-3-trifluoroacetamido-alpha-L-lyxo-h exopyranoside (6) with 3,4-di-O-acetyl-1,5-anhydro-2,6-dideoxy-L-lyxo-hex-1-enitol (1) or 4-O-acetyl-1,5-anhydro-3-O-benzyl-2,6-dideoxy-L-lyxo-hex-1-enit ol (2) in the presence of trimethylsilyl triflate/triethylamine gave alpha-(1----4)-linked disaccharide derivatives 7 and 8, respectively. In the presence of trimethylsilyl triflate only, 3,4-di-O-acetyl-1-O-tert-butyldimethylsilyl-2,6-dideoxy-beta-L-lyxo++ +-hexopyranose (3) and 6 gave mainly 7. Condensation of 1 or 2 with 9, obtained by O-deacylation of 8, afforded benzyl [O-(3,4-di-O-acetyl-2,6-dideoxy-alpha-L-lyso-hexopyranosyl)-(1----4)-O-( 3-O-benzyl-2,6-dideoxy-2,6-alpha-L-hexopyranosyl)-(1----4)-(2,3,6-tri deo xy-3-trifluoroacetamido-alpha-L-lyxo-hexopyranoside)] (11) and its 3''-benzyl analogue 12, respectively.