Novel isosteric, isopolar phosphonate analogs of oligonucleotides: preparation and properties.
A synthetic approach leading to novel-type modified oligothymidylates containing an isosteric, isopolar, enzyme-stable C3'-O-P-CH(2)-O-C4'' phosphonate alternative to phosphodiester internucleotide bond was elaborated. The suitable monomers were prepared from 4'-phosphonomethoxy derivatives of alpha-L-threo and beta-D-erythro-2',5'-dideoxythymidine, which were considered interesting as structurally related to nucleoside 5'-monophosphates. The phosphotriester method was applied to the automated synthesis of both homooligomeric phosphonate 15-mer chains and alternating phosphonate-phosphate constructs. The fully modified homooligomers did not hybridize while homooligomers with alternating sequences containing alpha-L-threo-configured units (but not beta-D-erythro-) showed a significant decrease in T(m) values in comparison with natural dT(15). For a comparative study, phosphodiester 4'-CH(3)-substituted oligothymidylate was synthesized and physical studies (NMR, CD, MDS modeling) were undertaken to shed more light on the changes in conformational behavior arising from the chosen structural alterations.
Tocík
Zdenek
Z
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo 2, 16610 Prague 6, Czech Republic.
Barvík
Ivan
I
Budesínský
Milos
M
Rosenberg
Ivan
I
D002942:Circular Dichroism; D003198:Computer Simulation; D019281:Dimerization; D008956:Models, Chemical; D008958:Models, Molecular; D009841:Oligonucleotides / Q000737:chemistry*; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D009841:Oligonucleotides; D063065:Organophosphonates