Nucleosides and nucleotides. Part 214: thermal stability of triplexes containing 4'alpha-C-aminoalkyl-2'-deoxynucleosides.
In order to develop novel antigene molecules forming thermally stable triplexes with target DNAs and having nuclease resistance properties, we synthesized oligodeoxynucleotides (ODNs) with various lengths of aminoalkyl-linkers at the 4'alpha position of thymidine and the aminoethyl-linker at the 4'alpha position of 2'-deoxy-5-methylcytidine. Thermal stability of triplexes between these ODNs and a DNA duplex was studied by thermal denaturation. The ODNs containing the nucleoside 2 with the aminoethyl-linker or the nucleoside 3 with the aminopropyl-linker thermally stabilized the triplexes, whereas the ODNs containing the nucleoside 1 with the aminomethyl-linker or the nucleoside 4 with the 2-[N-(2-aminoethyl)carbamoyl]oxy]ethyl-linker thermally destabilized the triplexes. The ODNs containing 2 were the most efficient at stabilizing the triplexes with the target DNA. The ODNs containing 4'alpha-C-(2-aminoethyl)-2'-deoxy-5-methylcytidine (5) also efficiently stabilized the triplexes with the target DNA. Stability of the ODN containing 5 to nucleolytic hydrolysis by snake venom phosphodiesterase (a 3'-exonuclease) was studied. It was found that the ODN containing 5 was more resistant to nucleolytic digestion by the enzyme than an unmodified ODN. In a previous paper, we reported that the ODNs containing 2 were more resistant to nucleolytic digestion by DNase I (an endonuclease) than the unmodified ODNs. Thus, it was found that the ODNs containing 4'alpha-C-(2-aminoethyl)-2'-deoxynucleosides were good candidates for antigene molecules.
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Naoko
N
Atsumi
Yoshihito
Y
Ueno
Makiko
M
Kanazaki
Satoshi
S
Shuto
Akira
A
Matsuda
D004247:DNA / Q000138:chemical synthesis* / Q000737:chemistry; D003850:Deoxyribonuclease I / Q000378:metabolism / Q000494:pharmacology; D003853:Deoxyribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D004355:Drug Stability; D006358:Hot Temperature; D006868:Hydrolysis; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D009693:Nucleic Acid Hybridization; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D003853:Deoxyribonucleosides; D009838:Oligodeoxyribonucleotides; C051802:triplex DNA; D004247:DNA; D003850:Deoxyribonuclease I; D010727:Phosphoric Diester Hydrolases; D043264:Phosphodiesterase I; C470790:phosphodiesterase I, snake venom