Hydrolytic (in)stability of phosphate isosteres

For decades enzymatic hydrolysis of nucleotides, a cornerstone of life, was studied extensively along with the chemical hydrolytic reaction. The metabolic instability of nucleotides, in contrast with their enormous chemical stability, triggered development of metabolically stable phosphate isosteres...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2022-12, Vol.244, p.114836-114836, Article 114836
Main Authors: Nassir, Molhm, Isaak, Avinoam, Fischer, Bilha
Format: Article
Language:English
Subjects:
Conformational analysis
Hydrolytic stability
Kinetics
Nucleotides
Phosphate isosteres
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Summary:For decades enzymatic hydrolysis of nucleotides, a cornerstone of life, was studied extensively along with the chemical hydrolytic reaction. The metabolic instability of nucleotides, in contrast with their enormous chemical stability, triggered development of metabolically stable phosphate isosteres. However, their chemical stability has not been reported. Here, we fill this gap by exploring the hydrolytic stability of the thiophosphate (PS) and dithiophosphate (PS2) monoester isostere families. Kinetic experiments with uridine-PS and -PS2 (UMPS and UMPS2) allow to chart their borders of stability. Furthermore, characterization of several chemical and structural features of UMPS and UMPS2 provide insights, which explain the dramatically different stability of PS or PS2 moieties at different positions of the nucleotide phosphate chain. Our conclusions may guide the broad scientific community that applies phosphate isosteres and allow the selection of optimal isosteres. [Display omitted] •Nucleotide isosteres reduce the metabolic instability of nucleotides.•The chemical stability of nucleotide isosteres is understudied.•We fill this gap by exploring the hydrolytic (in)stability of these isosteres.•We explain stability differences among common thio- and dithio-phosphate isosteres.•Our conclusions help select the proper phosphate isosteres.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2022.114836