Tetrahedron Vol. 41, No. 26, pp. 4693-4708.1991 oo4o420/91 $3.00+.00 Printedin Great Britain 0 1991 Pergamon press plc SPECTROSCOPIC, KINETIC AND SEMIEMPIRICAL MOLECULAR ORBITAL STUDIES ON S-AMINO-, &METHYLAMINO- & 8-DIMETHYLAMINO-ADENOSINES J. Hovinen, C. Glemarec, A. Sandsttijm, C. Sund, & J. Chattopadhyaya* Department of Bioorganic Chemistry, Box 58 1, Biomedical Center, University of Uppsala, S-751 23 Uppsala, Sweden (Received in UK 7 February 1991) Summary: Kinetic studies on acidic depurination of 8-aminoadenosine, 8-methylaminoadenosine, and 8- dimethylaminoadenosine show their relative rates are respectively 2.7,2 and 429,fold with respect ta adenosine. Structural consequence of 8-amino, 8-methylamino or 8-dimethylamino group in the g-substituted purine nucleosides have been therefore investigated in order to delineate the injluence of these d-amino substituents on the relative rate of cleavage of glycosyl bond under acidic condition by both IsN- and IH-NMR spectroscopy in neutral and acidic solutions. ISN-NiURstudies showed that the relative amount of protonation at Nl in 8-amine adenosine and B-methylaminoadenosine are 66% (4470 N’H+) and 8.5% (15% N’H+), respectively, while it is 96% (4% N7H+) in case of 8-dimethylaminoadenosine. IH-NMR studies also showed some differences in conformation of sugar moiety of nucleosides in acidic solution in comparison with their con$ormations in neutral solution. Semiempirical Molecular Orbital calculations have been used to throw light on steric and electronic factors dictated by a-amino, 8-methylamino or 8-dimethylamino group across CB-N8 bond that control the stabilization of N7H+ versus NlH+ species. Result from these Semiempirical Molecular Orbital calculations have been subsequently assessed with those obtained by IsN-NMR studies. Successful rational design of new analogues of nucleosides which should interfere specifically with the biosynthesis of DNA or RNA in cancer cells or virus- or parasite-infected cells requires that the effect of specific structural modification in these analogues on the chemical reactivities, hydrolytic stabilitities, and conformational properties in solution are clearly defined. In this respect, we considered 8-aminoadenosine, 8- methylaminoadenosine, and 8-dimethylaminoadenosine as useful target nucleosides because of the following reasons. Lipophilic derivatives of cytosine and guanosine have been shown to form Watson-Crick type base pairs in nonaqueous solvents over a wide temperature range suggesting that the monomers can be used to understand and possibly to predict structures of polymeric nucleic acids’, since low dielectric solvents mimic the dielectric environment of the interior of a nucleic acid double helix. Lipophilic derivatives of 8-amino-2’- deoxyadenosine and 8-methylamino-2’-deoxyadenosine are expected to form both Watson-Crick and Hcogsteen type base pairs with lipophilic thymidine derivative in non-polar solution while 8-dimethylamino-2’- deoxyadenosine should not. Our initial studies on the base-pairing abilities of lipophilic 8-amino-2’- deoxyadenosine derivative with lipophilic thymidine derivative in CDC13 have shown that their hydrogen- bonded complexation in 1: 1 and 1: 2 molar stoicheiometries at -20 “C are differentx. These studies have indicated that oligonucleotide based on 8-amino-2’-deoxyadenosine or 8-methylamino-2’-deoxyadenosine should form intermolecular DNA triplexes which have been shown to be important because of their potential role in chromosome mapping3 and in antisense gene therapfl. Our unpublished work has shown that the glycosidic bond of 8-amino-2’-deoxyadenosine [8-A-2,&I] and 8-methylamino-2’-deoxyadenosine [8-mA-2’-dA] are -10 times more acid-labile than that of the parent 2’-deoxyadenosine, which suggests that no acid-labile protecting group can be used in the synthesis of [8-A-2’-dA 18 & [S-mA-2’-dA]g. These observations prompted us to study the structural properties of 8-amino- & 8-alkylamino substituted adenosine and guanosine derivatives in 4693