Hydrolytic (in)stability of phosphate isosteres

Molhm Nassir; Avinoam Isaak; Bilha Fischer

doi:10.1016/j.ejmech.2022.114836

Hydrolytic (in)stability of phosphate isosteres

Molhm Nassir, Avinoam Isaak, Bilha Fischer

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.

Original language	English
Article number	114836
Journal	European Journal of Medicinal Chemistry
Volume	244
DOIs	https://doi.org/10.1016/j.ejmech.2022.114836
State	Published - 15 Dec 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Masson SAS

Funding

The conformation around the glycosidic bond – χ angle – was obtained by monitoring the vicinal coupling constants 3JC6-H1’ and 3JC2-H1’, extracted from 13C NMR spectra. A value of 3JC2-H1’ < 3JC6-H1’ indicates that χ is in the anti-conformation, whereas the reverse indicates that it is in the syn conformation [46]. The J-coupling constants in Table S1 provide strong support for the preferred anti-conformer in solution for UMPS2, UMPS and UMP 24–26. The following equations according to Ippel et al. were used to calculate the glycosidic bond angle χ for 24–26 [46].This work was supported by the German Israeli Foundation (I-1450-207.9/2018). The authors thank Dr. Yuval Elias for careful editing, and Dr. Natalie Pariente-Cohen for her kind assistance. This work was supported by the German Israeli Foundation ( I-1450-207.9/2018 ). The authors thank Dr. Yuval Elias for careful editing, and Dr. Natalie Pariente-Cohen for her kind assistance.

Funders	Funder number
German Israeli Foundation	I-1450-207.9/2018
UMPS	UMP 24–26

Keywords

Conformational analysis
Hydrolytic stability
Kinetics
Nucleotides
Phosphate isosteres

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title = "Hydrolytic (in)stability of phosphate isosteres",

abstract = "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.",

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AU - Nassir, Molhm

AU - Isaak, Avinoam

AU - Fischer, Bilha

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N2 - 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.

AB - 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.

KW - Conformational analysis

KW - Hydrolytic stability

KW - Kinetics

KW - Nucleotides

KW - Phosphate isosteres

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Hydrolytic (in)stability of phosphate isosteres

Abstract

Bibliographical note

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Keywords

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