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

Full text not available from this repository.

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:	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

Citation Data

Cited 5 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item