The synthesis of anti-fixed 3-methyl-3-deaza-2'-deoxyadenosine and other 3H-imidazo[4,5-c]pyridine analogs.
Rotation of a heterocyclic base around a glycosidic bond allows the formation of syn and anti conformations in nucleosides. The syn conformation has been observed primarily in purine-purine mismatches in DNA duplexes. Such mismatches give rise to false positive oligonucleotide hybridization in DNA-based diagnostics. Here we describe the synthesis of an analog of 2'-deoxyadenosine that retains its Watson-Crick functional groups, but cannot form the syn conformation. In this analog, the N3 atom of 2'-deoxyadenosine is replaced by a C-CH3 group to give 7-methyl-1-beta-D-deoxyribofuranosyl-1H-imidazo[4,5-c]pyridin-4-ylamine or 3-methyl-3-deaza-2'-deoxyadenosine (3mddA). This modification sterically prevents the syn conformation and 3mddA becomes an anti-fixed nucleoside analog of 2'-deoxyadenosine. The synthesis and conformational analysis of 3mddA and several analogs with an 3H-imidazo[4,5-c]pyridine skeleton are described, as well as their potential applications.
Irani
Rostem J
RJ
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA.
SantaLucia
John
J
D020029:Base Pairing; D004247:DNA / Q000138:chemical synthesis / Q000737:chemistry*; D003839:Deoxyadenosines / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis*; D013237:Stereoisomerism
C476875:3-methyl-3-deaza-2'-deoxyadenosine; D003839:Deoxyadenosines; D011725:Pyridines; D004247:DNA