Reactivity of Diphenylpropynone Derivatives Toward Metal-Associated Amyloid-尾 Species

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• 作者：Amit S. Pithadia ; Akiko Kochi ; Molly T. Soper ; Michael W. Beck ; Yuzhong Liu ; Sanghyun Lee ; Alaina S. DeToma ; Brandon T. Ruotolo ; Mi Hee Lim
• 刊名：Inorganic Chemistry
• 出版年：2012
• 出版时间：December 3, 2012
• 年：2012
• 卷：51
• 期：23
• 页码：12959-12967
• 全文大小：510K
• 年卷期：v.51,no.23(December 3, 2012)
• ISSN：1520-510X

文摘

In Alzheimer鈥檚 disease (AD), metal-associated amyloid-尾 (metal鈥揂尾) species have been suggested to be involved in neurotoxicity; however, their role in disease development is still unclear. To elucidate this aspect, chemical reagents have been developed as valuable tools for targeting metal鈥揂尾 species, modulating the interaction between the metal and A尾, and subsequently altering metal鈥揂尾 reactivity. Herein, we report the design, preparation, characterization, and reactivity of two diphenylpropynone derivatives (DPP1 and DPP2) composed of structural moieties for metal chelation and A尾 interaction (bifunctionality). The interactions of these compounds with metal ions and A尾 species were confirmed by UV鈥搗is, NMR, mass spectrometry, and docking studies. The effects of these bifunctional molecules on the control of in vitro metal-free and metal-induced A尾 aggregation were investigated and monitored by gel electrophoresis and transmission electron microscopy (TEM). Both DPP1 and DPP2 showed reactivity toward metal鈥揂尾 species over metal-free A尾 species to different extents. In particular, DPP2, which contains a dimethylamino group, exhibited greater reactivity with metal鈥揂尾 species than DPP1, suggesting a structure-reactivity relationship. Overall, our studies present a new bifunctional scaffold that could be utilized to develop chemical reagents for investigating metal鈥揂尾 species in AD.