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Density functional theory calculation of cyclic carboxylic phosphorus mixed anhydrides as possible intermediates in biochemical reactions: Implications for the Pro-Tide approach

Ricci, Antonio and Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419 2012. Density functional theory calculation of cyclic carboxylic phosphorus mixed anhydrides as possible intermediates in biochemical reactions: Implications for the Pro-Tide approach. Journal of Computational Chemistry 33 (10) , pp. 1029-1037. 10.1002/jcc.22934

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Abstract

Cyclic acyl phosphoramidates (CAPAs) are important components in several fundamental biological reactions such as protein synthesis and phosphorylation. These structures are particularly interesting in the nucleotide pro-drug approach, Pro-Tide, since they are putative intermediates in one of the hydrolysis steps required for activation. The central role played by the amino acid carboxylate function suggests first the formation of a cyclic mixed phosphorus anhydride, rapidly followed by water attack. To investigate such speculations, we performed quantum mechanical calculations using the B3LYP/6-311+G** level of theory for the plausible mechanisms of action considered. In the five-membered ring case, transition state theory demonstrated how the overall, gas-phase, mechanism of action could be split into two in-line addition-elimination (A-E) steps separated by a penta-coordinate phosphorane intermediate. The difference between five-membered and six-membered ring first A-E was also explored, revealing a single step, unimolecular reaction for the six-membered ring A-E profile. Implicit solvent contribution further confirmed the importance of CAPAs as reactive intermediates in such kind of reactions. Lastly, the second A-E pathway was analyzed to understand the complete pathway of the reaction. This analysis is the first attempt to clarify the putative mechanism of action involved in the activation of Pro-Tides and casts light also on the possible mechanism of action involved in primordial protein syntheses, strengthening the hypothesis of a common cyclic mixed phosphorus anhydride species as a common intermediate.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: cyclic acyl phosphoramidate; Pro-Tide; density functional theory; penta-coordinate phosphorane; in-line mechanism
Publisher: Wiley
ISSN: 1096-987X
Last Modified: 05 Jan 2024 05:52
URI: https://orca.cardiff.ac.uk/id/eprint/40761

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