Evaluating Fmoc-amino acids as selective inhibitors of butyrylcholinesterase

Abstract

Cholinesterases are involved in neuronal signal transduction, and perturbation of function has been implicated in diseases, such as Alzheimer’s and Huntington’s disease. For the two major classes of cholinesterases, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), previous studies reported BChE activity is elevated in patients with Alzheimer’s disease, while AChE levels remain the same or decrease. Thus, the development of potent and specific inhibitors of BChE have received much attention as a potential therapeutic in the alleviation of neurodegenerative diseases. In this study, we evaluated amino acid analogs as selective inhibitors of BChE. Amino acid analogs bearing a 9-fluorenylmethyloxycarbonyl (Fmoc) group were tested, as the Fmoc group has structural resemblance to previously described inhibitors. We identified leucine, lysine, and tryptophan analogs bearing the Fmoc group as selective inhibitors of BChE. The Fmoc group contributed to inhibition, as analogs bearing a carboxybenzyl group showed ~tenfold higher values for the inhibition constant (KI value). Inclusion of a t-butoxycarbonyl on the side chain of Fmoc tryptophan led to an eightfold lower KI value compared to Fmoc tryptophan alone suggesting that modifications of the amino acid side chains may be designed to create inhibitors with higher affinity. Our results identify Fmoc-amino acids as a scaffold upon which to design BChE-specific inhibitors and provide the foundation for further experimental and computational studies to dissect the interactions that contribute to inhibitor binding.

Unnatural Phosphorus‐Containing α‐Amino Acids and Their N‐FMOC Derivatives: Synthesis and In Vitro Investigation of Anticholinesterase Activity

“…Inclusion of a t ‐butoxycarbonyl on the side chain of Fmoc tryptophan led to an eightfold lower K I value compared to Fmoc tryptophan alone suggesting that modifications of the α‐amino acid side chains may be designed to create inhibitors with higher affinity. Their results identify Fmoc‐amino acids as a scaffold upon which to design BChE‐specific inhibitors and provide the foundation for further experimental and computational studies to dissect the interactions that contribute to inhibitor binding [26,27] …”

“…[28] Based on the afore mentioned, the purpose of this work was to carry out the synthesis of unnatural enantiomerically enriched α-amino acids containing phosphorus, their Fmoc derivatives and to study the anticholinesterase activity. [29] The synthesis of enantiomerically entiched α-amino acids is important since α-amino acids are suitable for the use only in the form of enantiomerically enriched isomers both in PET diagnostics and in the fields of medicine and pharmacy. Usually, the optical mirror image (enantiomer) of the pharmacologically active form either has no pharmacological activity or, at best, stays inactive.To create these α-amino acids, recent advancements have harnessed the distinctive capabilities of square planar Ni(II) complexes formed with Schiff bases derived from α-amino acids and chiral carbonyl derivatives of both (S)-and (R)-prolines.…”

“…Their results identify Fmoc-amino acids as a scaffold upon which to design BChE-specific inhibitors and provide the foundation for further experimental and computational studies to dissect the interactions that contribute to inhibitor binding. [26,27] Indeed, a previous study conducted by Zhao and colleagues explored a range of derivatives of β-carboline and quinolone alkaloids that share structural similarities with the Fmoc fragment, and they identified several compounds that exhibited inhibitory effects on BuChE and/or AChE. [28] Based on the afore mentioned, the purpose of this work was to carry out the synthesis of unnatural enantiomerically enriched α-amino acids containing phosphorus, their Fmoc derivatives and to study the anticholinesterase activity.…”

“…Based on the afore mentioned, the purpose of this work was to carry out the synthesis of unnatural enantiomerically enriched α‐amino acids containing phosphorus, their Fmoc derivatives and to study the anticholinesterase activity [29] …”

Synthesis, experimental andin silicostudies ofN-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, coupled with CSD data: a survey of interactions in the crystal structures of Fmoc–amino acids

“…The Fmoc moiety exhibits a structural affinity for the active sites of cholinesterases (acetylcholinesterase and butyrylcholinesterase). Therefore, Fmoc-AAs are attractive scaffolds for further development (Gonzalez et al, 2016;Ramirez et al, 2018;Pingul et al, 2019).…”