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Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition

Authors
  • Cavalloro, Valeria1, 2
  • Russo, Katia1
  • Vasile, Francesca
  • Pignataro, Luca
  • Torretta, Archimede3
  • Donini, Stefano3
  • Semrau, Marta S.4
  • Storici, Paola4
  • Rossi, Daniela1
  • Rapetti, Federica5
  • Brullo, Chiara5
  • Parisini, Emilio3, 6
  • Bruno, Olga5
  • Collina, Simona1
  • 1 (D.R.)
  • 2 Department of Earth and Environmental Sciences, University of Pavia, 27100 Pavia, Italy
  • 3 (E.P.)
  • 4 (P.S.)
  • 5 (O.B.)
  • 6 Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia
Type
Published Article
Journal
Molecules
Publisher
MDPI AG
Publication Date
Feb 19, 2020
Volume
25
Issue
4
Identifiers
DOI: 10.3390/molecules25040935
PMID: 32093112
PMCID: PMC7070305
Source
PubMed Central
Keywords
License
Green

Abstract

Alzheimer’s disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well-established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE). In recent years, GEBR-32a has been shown to possess selective inhibitory properties against PDE type 4 family members, resulting in an improvement in spatial memory processes without the typical side effects that are usually correlated with this mechanism of action. In this work, we performed the HPLC chiral resolution and absolute configuration assignment of GEBR-32a. We developed an efficient analytical and semipreparative chromatographic method exploiting an amylose-based stationary phase, we studied the chiroptical properties of both enantiomers and we assigned their absolute configuration by 1H-NMR (nuclear magnetic resonance). Lastly, we measured the IC50 values of both enantiomers against both the PDE4D catalytic domain and the long PDE4D3 isoform. Results strongly support the notion that GEBR-32a inhibits the PDE4D enzyme by interacting with both the catalytic pocket and the regulatory domains.

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