G. Fulcrandelkattan et al., CARBORANYL OLIGONUCLEOTIDES .2. SYNTHESIS AND PHYSICOCHEMICAL PROPERTIES OF DODECATHYMIDYLATE CONTAINING 5-(O-CARBORAN-1-YL)-2'-DEOXYURIDINE, Journal of the American Chemical Society, 116(17), 1994, pp. 7494-7501
Base modified oligothymidylates d(T)(12) containing one or more 5-(o-c
arboran-1-yl)-2'-deoxyuridine (CDU) instead of thymidine were synthesi
zed using an automated beta-cyanoethyl phosphoramidite approach. The t
hermostability of duplexes formed by these new oligonucleotides with n
atural complementary strand d(A)(12) and poly(rA) was affected by the
location of the carboranyl nucleotide within the chain. CDUd(T)(11) ol
igomer modified at the 5'-terminus displayed a melting temperature (T-
m = 28 degrees C) similar to natural d(T)(12) ((T)m = 29 degrees C), w
hereas 3'-modified d(T)(10)CDUd(T) and centrally modified d(T)(6)CDUd(
T)(5) oligonucleotide had lower T-m values (Tm = 20.5 and 15.3 degrees
C, respectively). The T-m studies were supported by molecular modelin
g of a duplex containing d(T)(6)CDUd(T)(5), which showed steric intera
ctions between the boron cage and 5'-adjacent base. As an added benefi
t, CDU modification at the 3'-terminus of the oligomers markedly incre
ased their resistance toward 5'-exonuclease activity, as determined by
half-life (t(1/2)) measurements. The t(1/2) increased in the order d(
T)(12) < d(T)(10)CDUd(T) << d(T)(9)CDU(2)d(T). The presence of one or
more carborane clusters in these new compounds increases their lipophi
licity and makes them potential candidates for boron neutron capture t
herapy (BNCT) and antisense oligonucleotide technology (AOT).