Ab initio quantum mechanical and X-ray crystallographic studies of gemcitabine and 2′-deoxy cytosine

Abstract Gemcitabine 2′,2′-difluoro 2′-deoxy cytosine (GEM) is a novel nucleoside which has demonstrated broad preclinical anti-cancer activity and appears promising in early stage human clinical trials. One purpose of this study was to characterize the energetically favored conformational modes of GEM by means of ab initio quantum mechanical studies with comparison to a novel X-ray crystallographic structure, and to determine the performance of ab initio quantum mechanical theory by comparison with X-ray structural data for GEM and 2′-deoxy cytosine (CYT). Another objective of this study was to attempt to determine key structural and electronic atomic interactions relating to the 2′,2′-difluoro substitution in GEM by the application of ab initio quantum mechanical methods. To our knowledge, these are the first reported ab initio quantum mechanical geometry optimizations of nucleosides using large (e.g. 6-31G ∗ ) slit valence function basis sets. The development of accurate physicochemical models on a small scale enables us to extend our studies of GEM to more complex studies including DNA incorporation, deamination, ribonucleotide reductase inhibition, and triphosphorylation.