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

Authors

  • Antonio Ricci,

    Corresponding author
    1. The Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom
    • The Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom
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  • Andrea Brancale

    Corresponding author
    1. The Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom
    • The Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom
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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. © 2012 Wiley Periodicals, Inc.

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