CONFORMATIONAL STUDIES OF THYMIDINE DIMERS CONTAINING SULFONATE AND SULFONAMIDE LINKAGES BY NMR-SPECTROSCOPY

The conformations of 3'-azido-terminated-sulfonate-dimer 1 and 3-amino-terminated-sulfonamide-dimer 2 are characterized by the following features: (1) The 5'-terminal nucleoside moiety of 1 has a S-type sugar (87% S), a staggered gamma+ rotamer across the C4'-C5' bond (65%) and an anti orientation of the base about the glycosidic bond. The 5'-terminal nucleoside moiety of 2 has an almost equal population of S and N conformations, a staggered gamma+ rotamer (69%) and an anti orientation of the base. (2) The 3'-terminal nucleoside moieties of 1 and 2 are in approximately 50% N reversible S equilibrium and the gamma(t) conformer is the most populated. A comparison of the conformational properties of 1 and 2 with the natural thymidylyl(3'-->5)thymidine [d(TpT)] 3, thymidylyl-(3'-->5)-5'-thio-5'-deoxythymidine d(TpST)5 4 and thymidinylacetamido-[3'(O)-->5(C)]-5-deoxythymidine NH2d(TcmT)5 5, show the following characteristics: (i) The conformational preference of the sugar ring is partially determined by the gauche effect. This means that the more polar the C3-X bond due to the electronegative character of the 3-alpha-X substituent. the more the N reversible S equilibrium is biased toward the S-type conformation: 3'-O-S > 3'-O-P > 3'-O-H > 3'-N3 > 3-NH2. (ii) The conformation about the C4'-C5'bond (gamma) is also influenced by the gauche effect based on the nature of the 5-substituent and by the ability of the 5'-substituent to form hydrogen bonding with the H6 of thymine. Thus, the population of the gamma+ conformer follows the order: 5'-O > 5-N > 5-S > 5'-C. (iii) The C5'-C6' bond has a slight preference for the beta(t) conformation (56% beta(t) in 1 and 58% beta(t) in 2), while in natural d(TpT) 3, the C5'-O5'bond accounts for 83% of beta(t) conformation. Upon substitution of the 5-oxygen by 5'-sulfur, as in d(TpST) 4, the population of beta(t) conformer was found to decrease to 57%. This decrease in the beta(t) population in 1, 2 and 4 is a result of the reduced polarity of the 5-C-X [X = CH2 in 1 and 2 and X = S in 4] in comparaison to the 5-C-O bond in 3, which weaken the gauche effect.