AB-INITIO QUANTUM-MECHANICAL AND X-RAY CRYSTALLOGRAPHIC STUDIES OF GEMCITABINE AND 2'-DEOXY CYTOSINE

Gemcitabine 2',2'-difluoro 2'-deoxy cytosine (GEM) is a novel nucleosi de which has demonstrated broad preclinical anti-cancer activity and a ppears promising in early stage human clinical trials. One purpose of this study was to characterize the energetically favored conformationa l modes of GEM by means of ab initio quantum mechanical studies with c omparison to a novel X-ray crystallographic structure, and to determin e the performance of ab initio quantum mechanical theory by comparison with X-ray structural data for GEM and 2'-deoxy cytosine (CYT). Anoth er objective of this study was to attempt to determine key structural and electronic atomic interactions relating to the 2',2'-difluoro subs titution in GEM by the application of ab initio quantum mechanical met hods. 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 ph ysicochemical models on a small scale enables us to extend our studies of GEM to more complex studies including DNA incorporation, deaminati on, ribonucleotide reductase inhibition, and triphosphorylation. Copyr ight (C) 1996 Elsevier Science Ltd