Tailoring Peptide–Nucleotide Conjugates (PNCs) for Nucleotide Delivery in Bacterial Cells

Abstract

The design and synthesis of peptide‐2′‐deoxythymidine‐5′‐O‐monophosphate conjugates as potential active delivery systems for nucleotides into auxotrophic E. coli strains is presented. A series of oligopeptides were allowed to react with 5′‐O‐(dibenzylphosphate)‐2′‐deoxythymidine or its suitably 3′‐derivatized analogues to give the relevant peptide–nucleotide adducts, by the formation of a biolabile chemical connection. Using strategies based on the principles of orthogonal protection and activation, rational variations were made to the linker and the peptide moiety in order to tune the metabolic stability of the conjugates.

The case of triethylammonium cation loss during purification of certain nucleotide analogues: a cautionary note

“…Interestingly, incidents of non-stoichiometric amounts of the TEAH + counterion in purified compounds can be found in the literature. For example, 5′-monophosphates of a series of nucleoside derivatives were obtained by high-performance liquid chromatography (HPLC) purification in triethylammonium bicarbonate buffer followed by a repeated lyophilization from water and were expected to be in the form of bis-TEAH + salts [ 10 ]. According to the integration of the appropriate signals in 1 H NMR spectra, in most cases, about two equiv.…”

“…However, for two phosphate monoesters, only one equiv. of TEAH + cation can be found in the spectra (triethylammonium salts of 3′- O -[ N -For-Gly- l -β-amino-Ala-(β-carbamate)- l -Phe-OMe] and 3′- O -[ N -For- l -Met- l -Lys-(ε-carbamate)- l -Ala- l -Ala- l -Phe-OMe] derivatives of 2′-deoxythymidine-5′-monophosphate) [ 10 ], and this suggests that during lyophilization, melting of the material could take place, allowing the equilibrium ( 1 ) to proceed. Conversely, four or more equiv.…”

“…Conversely, four or more equiv. of TEA found in some other cases (triethylammonium salts of 3′- O -[ N -For- l -Met- l -Lys-(ε-carbamate)- l -Lys-(ε-NH 2 )-OMe], 3′- O -[ N -For- l -Met- l -Glu-(methyloxy-δ-carboxamide)-OMe], and 3′- O -[ N -For- l -Met- l -Glu-(δ-ester)- l -Phe-OMe] derivatives of 2′-deoxythymidine-5′-monophosphate) [ 10 ] indicated incomplete removal of the base or its salts.…”

MgI2‐chemoselective cleavage for removal of amino acid protecting groups: A fresh vision for peptide synthesis

“…The Boc group could also be removed from Boc‐Trp(For)‐OH, without affecting the N ‐in formyl moiety (Table , entry 13). It is well known that a t ‐butyl ester or a Boc N ‐protecting group, are more sensitive to acidic conditions than a N ‐benzoyl or a N ‐formyl group . The same occurred in the MgI 2 ‐MW mediated cleavage.…”

Syntheses of 5′‐Nucleoside Monophosphate Derivatives with Unique Aminal, Hemiaminal, and Hemithioaminal Functionalities: A New Class of 5′‐Peptidyl Nucleotides

“…[26] According to Route 2, thioethanol analogue 24 was formed by selective S-alkylation of the correspondinga cetoxyc ompound 12 with 2-mercaptoethanol in good yield (70 %), as shown in Scheme6.T he phosphoramidite approach could in theory be utilized for the synthesis of phosphoester 25;h owever, selectiveo xidationo fP III to P V in the presence of as ulfur atom posed ar eal challenge. [27] Therefore, the POCl 3 method was adopted instead, which involved the formationo fi ntermediate 10 from 3'-Obenzylt hymidine and its in situ treatment with thioethanola nalogue 24 in the presence of N-methyl imidazole. Quenching www.chemeurj.org followed by preparative RP-HPLC purification furnished phosphoester 25 as ad iastereoisomeric mixture in 66 %y ield over two steps.…”