Synthesis, Characterization, and Metal Coordinating Ability of Multifunctional Carbohydrate-Containing Compounds for Alzheimer's Therapy
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- 作者：Tim Storr ; Michael Merkel ; George X. Song-Zhao ; Lauren E. Scott ; David E. Green ; Meryn L. Bowen ; Katherine H. Thompson ; Brian O. Patrick ; Harvey J. Schugar ; Chris Orvig
- 刊名：Journal of the American Chemical Society
- 出版年：2007
- 出版时间：June 13, 2007
- 年：2007
- 卷：129
- 期：23
- 页码：7453 - 7463
- 全文大小：375K
- 年卷期：v.129,no.23(June 13, 2007)
- ISSN：1520-5126
文摘
Dysfunctional interactions of metal ions, especially Cu, Zn, and Fe, with the amyloid-
(A) peptideare hypothesized to play an important role in the etiology of Alzheimer's disease (AD). In addition to directeffects on A aggregation, both Cu and Fe catalyze the generation of reactive oxygen species (ROS) inthe brain further contributing to neurodegeneration. Disruption of these aberrant metal-peptide interactionsvia chelation therapy holds considerable promise as a therapeutic strategy to combat this presently incurabledisease. To this end, we developed two multifunctional carbohydrate-containing compounds N,N'-bis[(5--D-glucopyranosyloxy-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL1) and N,N'-bis[(5--D-glucopyranosyloxy-3-tert-butyl-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL2) for brain-directed metal chelation and redistribution. Acidity constants were determined by potentiometry aided byUV-vis and 1H NMR measurements to identify the protonation sites of H2GL1,2. Intramolecular H bondingbetween the amine nitrogen atoms and the H atoms of the hydroxyl groups was determined to have animportant stabilizing effect in solution for the H2GL1 and H2GL2 species. Both H2GL1 and H2GL2 were foundto have significant antioxidant capacity on the basis of an in vitro antioxidant assay. The neutral metalcomplexes CuGL1, NiGL1, CuGL2, and NiGL2 were synthesized and fully characterized. A square-planararrangement of the tetradentate ligand around CuGL2 and NiGL2 was determined by X-ray crystallographywith the sugar moieties remaining pendant. The coordination properties of H2GL1,2 were also investigatedby potentiometry, and as expected, both ligands displayed a higher affinity for Cu2+ over Zn2+ with H2GL1displaying better coordinating ability at physiological pH. Both H2GL1 and H2GL2 were found to reduceZn2+- and Cu2+- induced A1-40 aggregation in vitro, further demonstrating the potential of thesemultifunctional agents as AD therapeutics.
(A) peptideare hypothesized to play an important role in the etiology of Alzheimer's disease (AD). In addition to directeffects on A aggregation, both Cu and Fe catalyze the generation of reactive oxygen species (ROS) inthe brain further contributing to neurodegeneration. Disruption of these aberrant metal-peptide interactionsvia chelation therapy holds considerable promise as a therapeutic strategy to combat this presently incurabledisease. To this end, we developed two multifunctional carbohydrate-containing compounds N,N'-bis[(5--D-glucopyranosyloxy-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL1) and N,N'-bis[(5--D-glucopyranosyloxy-3-tert-butyl-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL2) for brain-directed metal chelation and redistribution. Acidity constants were determined by potentiometry aided byUV-vis and 1H NMR measurements to identify the protonation sites of H2GL1,2. Intramolecular H bondingbetween the amine nitrogen atoms and the H atoms of the hydroxyl groups was determined to have animportant stabilizing effect in solution for the H2GL1 and H2GL2 species. Both H2GL1 and H2GL2 were foundto have significant antioxidant capacity on the basis of an in vitro antioxidant assay. The neutral metalcomplexes CuGL1, NiGL1, CuGL2, and NiGL2 were synthesized and fully characterized. A square-planararrangement of the tetradentate ligand around CuGL2 and NiGL2 was determined by X-ray crystallographywith the sugar moieties remaining pendant. The coordination properties of H2GL1,2 were also investigatedby potentiometry, and as expected, both ligands displayed a higher affinity for Cu2+ over Zn2+ with H2GL1displaying better coordinating ability at physiological pH. Both H2GL1 and H2GL2 were found to reduceZn2+- and Cu2+- induced A1-40 aggregation in vitro, further demonstrating the potential of thesemultifunctional agents as AD therapeutics.