Methoxymethyl (MOM) Group Nitrogen Protection of Pyrimidines Bearing C-6 Acyclic Side-Chains

Simon M. Ametamey,Silvana Raić-Malić,Tobias L. Ross,Janez Plavec,Damjan Makuc,Martina Petrović,Svjetlana Krištafor,Tatjana Gazivoda Kraljević

doi:10.3390/molecules16065113

Abstract

Novel N-methoxymethylated (MOM) pyrimidine (4−13) and pyrimidine-2,4-diones (15−17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH3-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET).

Highlights

The pyrimidine moiety is a widespread heterocyclic unit which is found in several biologically active natural products, as well as synthetic pharmacophores with biological activities that show considerable therapeutic potential [1,2,3,4,5]
It was shown that N-1 and/or N-3-alkylated pyrimidine derivatives had a wide range of antiviral activity [9,10,11,12,13,14]
These compounds labelled with positron-emitting radioisotopes can be used as in situ reporter probes to allow non-invasive imaging of herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) gene expression using positron emission tomography (PET) [22,23,24,25]

Summary

Introduction

The pyrimidine moiety is a widespread heterocyclic unit which is found in several biologically active natural products, as well as synthetic pharmacophores with biological activities that show considerable therapeutic potential [1,2,3,4,5]. The structural diversity and biological importance of pyrimidines have made them attractive targets for synthesis over the years For this reason numerous analogues and derivatives of pyrimidines have been synthesized and developed as pharmacologically active compounds or drugs [6,7]. HSV-1 TK in combination with nucleoside analogue as fraudulent substrates can be used as suicide enzymes in gene therapy of cancer [19,20,21] These compounds labelled with positron-emitting radioisotopes can be used as in situ reporter probes to allow non-invasive imaging of HSV-1 TK gene expression using positron emission tomography (PET) [22,23,24,25]. Some C-6 fluoroalkylated pyrimidines exhibited pronounced cytostatic activities [31,32,33], while thymines with 6-(2,3-dihydroxypropyl) and

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Conclusion