Stereoelectronic effects in nucleosides and nucleotides

Abstract: This thesis is based on 12 original publications from 1994-98. Intramolecular stereoelectronicforces (anomeric and gauche effects), beside intermolecular forces such as hydrogen bonding,base stacking, electrostatics and hydration, have been found to be responsible for the localstructural changes of DNA and RNA and their components. A detailed insight into the stereoelectronic forces has been obtained by a systematic pairwise comparison of the thermodynamics in various N- and C-nucleosides at several pDs, determined from pseudorotational analyses of 3JHH. This has allowed us to understand how the electronic character of various sugar substituents modulates the strengths of the stereoelectronic drive of the sugar conformation. Evidences have been put forward supporting that both the anomeric and gauche effects result from the appropriate orbital mixing rather than dipole-dipole interactions: the nucleobase-dependent anomeric effect results nO4'→Σ' C1'-N1/9 interaction, whereas the gauche effect originates from Σ→Σ' orbital mixing. It has been demonstrated that the modulations of the gauche and the anomeric effect are interrelated, and mutually influence each other, and the final outcome of the free-energy of the sugar conformational equilibrium is a result of this enthalpic interplay and of the entropy. The electronic character of the nucleobase at various pDs is transmitted to steer the sugar conformation in β-nucleosides owing to the modulation of the anomeric and gauche effects. The strength of the anomeric effect in α-nucleosides is reduced compared to β-counterparts owing to weaker overlap of O4' lonepairs with Σ' C1'N1/9. In C-nucleosides, the conformation of the sugar moiety is dictated by nO4' →Σ' C1'C5/9(sp2) interactions, which are reduced and enhanced at acidic and alkaline pDs. The strength of the nO4'→Σ' C1'-N1/9 anomeric effect in adenosine and guanosine and in their 2'-deoxy counterparts has been quantitated using 9-deazaadenosine as a reference point for the estimation of the counteracting steric effect of the nucleobase in the N-nucleosides. The interaction of 2'-OH with the vicinal phosphate results in a unique two-state (N,εt ) ↔ (S,ε-) equilibrium in 3'- ethylphosphate ribonucleotides whereas in 2'-deoxy counterparts no correlation between sugar and phosphate-backbone conformation could be detected.A quantitative Karplus-type equation for the translation of 3JHF into ΦHCCF has beenparametrized for the first time, taking into account effects of orientation and electronegativity of substituents and the influence of HCC and FCC bond angle changes. The application of this equation to pseudorotational analyses of 3JHF in combination with 3JHH has allowed to quantitatively describe the conformation of several antiviral and antitumour mono and difluoronucleosides.