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Site-Activated Chelators Derived from Anti-Parkinson Drug Rasagiline as a Potential Safer and More Effective Approach to the Treatment of Alzheimer’s Disease

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Abstract

chelators can modulate β-amyloid accumulation, protect against tau hyperphosphorylation, and block metal-related oxidative stress, and thereby hold considerable promise as effective anti-AD drugs. At present, a growing interest is focusing on increasing the efficacy and targeting of chelators through drug design. To this end, we have developed a new class of multifunctional prochelators from three FDA- approved drugs rasagiline, rivastigmine, and donepezil or tacrine. HLA20 A was designed by merging the important pharmacophores of rasagiline, rivastigmine, and donepezil into our newly developed multifunctional chelator HLA20. M30D was constructed using the key pharmacophoric moieties from rasagiline, rivastigmine, and tacrine. Experiments showed that both compounds possess potent anti-acetylcholinesterase (AChE) activity in vitro with weak inhibition of butyrylcholinesterase (BuChE), and without significant metal-binding activity. M30D was found also to be a highly potent MAO A inhibitor with moderate inhibition of MAO B in vitro. Both HLA20 and M30D can be activated by inhibition of AChE to release active chelators HLA20 and M30, respectively. HLA20 and M30 have been shown to be able to modulate amyloid precursor protein regulation and beta-amyloid reduction, suppress oxidative stress, and passivate excess metal ions (Fe, Cu, and Zn). Compared with the activated chelator HLA20 or M30, both HLA20A and M30D exhibited lower cytotoxicity in SH-SY5Y neuroblastoma cells, substantiating the prochelator strategy for minimizing toxicity associated with poor targeted chelators.

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Acknowledgments

We thank the Alzheimer Association (USA), Alzheimer Drug Discovery Foundation (New York, USA), Technion-Research and Development and the Weizmann Institute for generous support of this work.

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Author notes

  1. Hailin Zheng

    Present address: Department of Medicinal Chemistry, Intra-Cellular Therapies Inc, 3960 Broadway, New York, NY, 10032, USA

Authors and Affiliations

  1. Department of Organic Chemistry, The Weizmann Institute of Science, 76100, Rehovot, Israel

    Hailin Zheng & Mati Fridkin

  2. Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases and Department of Pharmacology, Technion-Rappaport Family Faculty of Medicine Haifa, 31096, Haifa, Israel

    Moussa B. H. Youdim

  3. Department of Biology, Yonsei World Central University, Seoul, South Korea

    Moussa B. H. Youdim

Authors
  1. Hailin Zheng
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  2. Mati Fridkin
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Corresponding authors

Correspondence to Mati Fridkin or Moussa B. H. Youdim.

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Dedication to Abel Lathja

I do not recall exactly when I first met Abel, but I think it was in Budapest many years ego. What I recall was the fact he was so complimentary to my work as young neurochemist and his encouragement throughout the years I have known him. I was very much moved and honored when decided to dedicate one volume of Neurochemical Research for my contributions and he wrote the most flattering preface. Besides his tremendous scientific contributions, it is his Hungarian charm and gentleness that I so admire, including his unflenching friendship. This has made him many friends and admires from all the world. Moussa B.H. Youdim.

Special Issue: In Honor of Dr. Abel Lajtha.

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Zheng, H., Fridkin, M. & Youdim, M.B.H. Site-Activated Chelators Derived from Anti-Parkinson Drug Rasagiline as a Potential Safer and More Effective Approach to the Treatment of Alzheimer’s Disease. Neurochem Res 35, 2117–2123 (2010). https://doi.org/10.1007/s11064-010-0293-1

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