O-(5',16)-METHANOCYTIDINE - SYNTHESIS, CONFORMATIONAL PROPERTIES AND DEAMINATION BY CYTIDINE DEAMINASE

The synthesis of O-5',O-6-methanocytidine (4), a pyrimidine nucleoside restricted to the anti conformation, is described. Molecular modeling studies suggest that 4 is more flexible than conventional cyclonucleo sides because of its larger-than-usual bridging system and that it can exist in a number of low energy conformations where the glycosyl rota tion angles (chi) cover an similar to 80 degrees segment of the anti r ange. However, while both N-type (C2'-exo) and S-type (C3'-exo) sugar puckerings are possible, none of the low energy conformers adopt the C 3'-endo or C2'-endo puckering modes generally seen for unconstrained n ucleosides. The lowest energy conformer predicted for 4 (chi = -152 de grees, gamma = 73 degrees, P = 206 degrees) is similar to the X-ray st ructure of a related compound, namely 5-hydroxy-O-5',O-6-methanouridin e (12, chi = -138 degrees, gamma = 63 degrees, P = 200 degrees). In so lution, NMR evidence suggests an equilibrium between C2'-exo and C3'-e xo puckerings for 4, and CD evidence suggests an average glycosyl rota tion angle (chi) of around -160 degrees. O-5',O-6-Methano-cytidine (4) is slowly deaminated by crude cytidine deaminase from mouse liver to give O-5',O-6-methanouridine (3). Assuming that 4 interacts with the n ormal active site, it is concluded that cytidine deaminase from that p articular source requires its ordinary substrates to adopt the anti co nformation.