Design, Synthesis, and Biological Evaluation of Hybrid Glypromate Analogues Using 2-Azanorbornane as a Prolyl and Pipecolyl Surrogate

  • ACS Chem Neurosci. 2021 Oct 6;12(19):3615-3624. doi: 10.1021/acschemneuro.1c00339.
Ivo E Sampaio-Dias  1 ,  Miguel Santejo  2 ,  Sara C Silva-Reis  1 ,  Márcia A Liz  2 ,  Cristina Alcoholado  3 ,  Manuel Algarra  4 ,  Xerardo García-Mera  5 ,  José E Rodríguez-Borges  1
Affiliations
  • 1. LAQV/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal.
  • 2. Neurodegeneration Team, Nerve Regeneration Group, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal, and i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
  • 3. Department of Cell Biology, Genetics and Physiology, Faculty of Sciences, University of Málaga, Campus de Teatinos, 29071 Málaga, Spain.
  • 4. Department of Inorganic Chemistry, Faculty of Sciences, University of Málaga, Campus de Teatinos, 29071 Málaga, Spain.
  • 5. Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, E-15782 Santiago de Compostela, Spain.
PMID: 34515466 DOI: 10.1021/acschemneuro.1c00339
Abstract

Neurodegenerative disorders of the central nervous system are a class of heterogeneous pathologies affecting millions of people worldwide and represent a global health burden in developed and developing countries. Without restorative treatments currently available, research on neuroprotective drugs is considered a health priority. In this study, new analogues of the glycyl-l-prolyl-l-glutamic acid (Glypromate) neuropeptide were designed, synthesized, and biologically evaluated using (1R,3S,4S)-2-azanorbornane-3-carboxylic acid as a hybrid construct of l-proline and l-pipecolic acid. Neuroprotection assays carried out in human neuroblastoma SH-SY5Y cells using 6-hydroxydopamine as a stress inducer showed great percentage of recovery (29.7-40.0%) at 100 μM. Among this series, [(1R,3S,4S)-2-glycyl-2-azanorbornane-3-carbonyl]-l-aspartic acid (2a) stands out with a remarkable percentage of recovery (40.0%, at 100 μM) and safe toxicological profile in SH-SY5Y and human adipose mesenchymal stem cells.

Keywords
GPE; glypromate; hybrid scaffolds; neuroprotective drugs; peptidomimetics.
Products