Effect of (5′S)-5′,8-cyclo-2′-deoxyadenosine on the conformation of di and trinucleotides. A NMR and DFT study

Abstract

5′,8-Purine cyclonucleosides constitute an important class of oxidatively generated tandem lesions whose formation involves initial hydroxyl radical-mediated hydrogen atom abstraction from the 5-hydroxymethyl group of 2-deoxyribose followed by intramolecular cyclization. The present study deals with the synthesis of the 5′S diastereomer of 5′,8-cyclo-2′-deoxyadenosine containing di- and tri-oligodeoxynucleotides as an attempt to delineate the conformational changes induced in the DNA fragments by the presence of a rigid modified nucleoside. For this purpose, extensive 1D and 2D NMR measurements that were completed by DFT theoretical calculations were performed. As a striking result, it was found that the covalent bond between C(5′) and C(8) in the investigated purine cyclonucleoside induces an unusual West (₀T¹) conformation of the furanose ring. Thus it can be postulated that the rigid structure of the tandem lesion would strongly perturb the global geometry of oligonucleotides at the site of the modification and therefore affect the enzymatic activity of DNA polymerases and repair enzymes.