Discovery of alkenylboronic acids as neuroprotective agents affecting multiple biological targets involved in Alzheimer's disease.

Alkenylboronic acids have shown important biological activities that contribute to neuroprotection. We have determined their influence on the β-amyloid (βA) aggregation process, β-secretase and acethylcholinesterase activities on cell-free systems, on the redox and lipid peroxidation status, and on the vulnerability to apoptotic death in an APPswe neuroblastoma cell line, before and after hydrogen peroxide treatment. We have discovered that 2-arylvinylboronic acids and some of their esters possess a set of properties which makes them highly useful as neuroprotective agents affecting multiple biological targets involved in AD. These properties are not paralleled by the related 2-arylboronic acids.

[1]  V. Tumiatti,et al.  Multitarget-directed ligands: innovative chemical probes and therapeutic tools against Alzheimer's disease. , 2011, Current topics in medicinal chemistry.

[2]  L. Lash Mitochondrial glutathione transport: physiological, pathological and toxicological implications. , 2006, Chemico-biological interactions.

[3]  I. Kanazawa,et al.  Autotaxin expression is enhanced in frontal cortex of Alzheimer-type dementia patients , 2006, Neuroscience Letters.

[4]  H. Esterbauer,et al.  Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. , 1991, Free radical biology & medicine.

[5]  L. Polgár,et al.  Low Barrier Hydrogen Bond Is Absent in the Catalytic Triads in the Ground State but Is Present in a Transition-state Complex in the Prolyl Oligopeptidase Family of Serine Proteases* , 1997, The Journal of Biological Chemistry.

[6]  D. Egan,et al.  Discovery and optimization of boronic acid based inhibitors of autotaxin. , 2010, Journal of medicinal chemistry.

[7]  T. Montine,et al.  Free radical-mediated damage to brain in Alzheimer's disease and its transgenic mouse models. , 2008, Free radical biology & medicine.

[8]  A. Lambeir,et al.  In situ prolyl oligopeptidase activity assay in neural cell cultures , 2012, Journal of Neuroscience Methods.

[9]  A. Meister,et al.  Origin and turnover of mitochondrial glutathione. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Boucher,et al.  Aminoboronic acids and esters: from synthetic challenges to the discovery of unique classes of enzyme inhibitors. , 2011, Chemical Society reviews.

[11]  G. Perry,et al.  β‐Site APP cleaving enzyme up‐regulation induced by 4‐hydroxynonenal is mediated by stress‐activated protein kinases pathways , 2005, Journal of neurochemistry.

[12]  H. Figueiredo,et al.  Thrombin Induces Surface and Intracellular Secretion of Amyloid Precursor Protein from Human Endothelial Cells , 1999, Thrombosis and Haemostasis.

[13]  Xin Meng,et al.  Role of oxidative stress and intracellular glutathione in the sensitivity to apoptosis induced by proteasome inhibitor in thyroid cancer cells , 2009, BMC Cancer.

[14]  H. Levine Small molecule inhibitors of Abeta assembly , 2007, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[15]  E. Masliah,et al.  Alzheimer's disease: recent advances and future perspectives. , 2012, Journal of Alzheimer's disease : JAD.