Nucleic-Acid Analogs with Restricted Conformational Flexibility in the Sugar-Phosphate Backbone('Bicyclo-DNA') Synthesis and Properties of Oligodeoxynucleotides Containing [3'S,5'S,6'R)-6'-Amino-2'-deoxy-3',5'-ethano-#beta#-D-ribofuranosyl]thymine(=

摘要

We describe the synthesis of the acetamido-and trifluoroacetamido-functionalized bicyclo-thymidines 11 and 12,starting from the silyl enol ether 1,in 6 steps.These nucleosides were converted to the corresponding cyanoethyl phosphoramidite building blocks 16 and 17 and subsequently incorporated into the homo-thymidylate decamers 18-22 Upon deprotection of the oligomers,the trifluoroacetamido functions were cleaved,leaving behind a free amino function in the sugar-phosphate backbone that is protonated at neutral pH,giving rise to partially zwitterionic oligonucleotides.Pairing properties with the complementary DNA oligomer d(A_(10)),as determined by UV/melting curves,revealed a slightly increased stability of the duplex d(A_(10)).20,in which the decathymidylate sequence shows an alternating arrangement of natural thymidine and amino-bicyclo-thymidine residues,relative to thenatural reference duplex.The dependence of T_mon the salt concentration of the medium is reduced in this case.Duplex destabilization occurs if the amino-bicyclo-thymidine residues are replaced by the charge-neutral acetamido-bicyclo-nucleosides(e.g.,d(A_(10)).22),most probably due to steric interference of the acetamido substituent with the backbone P-O(5')bond.