J . Am. Chem. SOC.1994, 116, 7494-7501
7494
Carboranyl Oligonucleotides. 2. Synthesis and Physicochemical Properties of Dodecathymidylate Containing 5-( o-Carboran- 1-yl)-2’-deoxyuridine+ Gdraldine Fulcrand-El Kattan,**lZbigniew J. Lesnikowski,**gSbijie Yao,11 Farial Tanious,ll W. David Wilson,ll and Raymond F. Schinazi*~*~~ Contribution from the Veterans Affairs Medical Center, Medical Research 151, Decatur, Georgia 30033, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, and Department of Chemistry, Georgia State University, Atlanta, Georgia 30303 Received November 23, 1993’
Abstract: Base modified oligothymidylates d(T)lz containing one or more 5-(o-carboran- l-y1)-2’-deoxyuridine (CDU) instead of thymidine were synthesizedusing an automated 8-cyanoethyl phosphoramiditeapproach. The thermostability of duplexes formed by these new oligonucleotides with natural complementary strand d(A)lz and poly(rA) was affected by the location of thecarboranyl nucleotide within the chain. CDUd(T)I 1 oligomer modified at the 5’-terminus displayed a melting temperature ( T , = 28 “C) similar to natural d(T)12 ( T , = 29 “C), whereas 3’-modified d(T)l&DUd(T) and centrally modified d(T)&DUd(T)s oligonucleotide had lower Tm values ( T , = 20.5 and 15.3 “C, respectively). The T , studies were supported by molecular modeling of a duplex containing d(T)&DUd(T)s, which showed steric interactions between the boron cage and 5’-adjacent base. As an added benefit, CDU modification a t the 3’-terminus of the oligomers markedly increased their resistance toward 5’-exonuclease activity, as determined by half-life (tllz) measurements. The t l l z increased in the order d(T)12 < d(T)&DUd(T)
