Unsaturated didehydrodeoxycytidine drugs. 1. Impact of C=C positions in the sugar ring

The chemical names of a pair of recently synthesized antitumor drugs are given in the present study as 1',2'-didehydro-3',4'-deoxycytidine and 3',4'-didehydro-2',4'-deoxycytidine. The order of stabilities, geometries, and ionization potentials of the unsaturated sugar-modified cytidine derivatives is investigated quantum mechanically. Our density functional theory calculations based on the B3LYP/6-311++G** model reveal that 3',4'-didehydro-2',4'-deoxycytidine (SD-C2) is slightly more stable than its isomer, 1',2'-didehydro-3',4'-deoxycytidine, by an energy of 5.28 kJ x mol(-1) in isolation. The isomers structurally differ by only the C=C location in the sugar ring. However, the compounds exhibit an unusual orientation with a less puckered sugar ring; that is, 3',4'-didehydro-2',4'-deoxycytidine is determined to be a beta-nucleoside, which is a C1'-endo, north conformer with an anticlinal sugar ring, whereas 1',2'-didehydro-3',4'-deoxycytidine is neither an alpha-nucleoside nor a beta-nucleoside but is a C4'-endo, south conformer with an antiperiplanar sugar ring. The present study further indicates that the C=C double bond location imposes significant effects on their ionization potentials (IPs) and other important molecular properties such as molecular electrostatic potential (MEP). In addition, inner shell binding energy spectral variations with respect to the C=C bond exhibit more site dependence. The valence shell binding energy spectral changes are, on the other hand, significant and delocalized. The latter indicates that such changes in valence space are not isolated effects but are within the entire nucleoside. Finally, the present study suggests that the nearly 0.6 eV difference in the first ionization potentials (highest occupied molecular orbital) of the isomers is sufficiently large to identify them by further spectroscopic measures.