[Design, synthesis and evaluation of polyamide-nucleoside hybrids and oligonucleotides conjugated hybrid as a novel gene expression control compound]

Yakugaku Zasshi. 2010 Mar;130(3):355-75. doi: 10.1248/yakushi.130.355.
[Article in Japanese]

Abstract

On the basis of reports that a minor groove binder pyrrolepolyamide can interfere with gene expression by the sequence-specific recognition of DNA, we expected that nucleoside bearing a pyrrolepolyamide would be able to regulate gene expression. Therefore, we designed and synthesized the pyrrolepolyamide-adenosine (Hybrid 1) and -2'-deoxyguanosine hybrids (Hybrid 2 and Hybrid 3) as lead compounds for gene expression control compounds. The pyrrolepolyamide frame of Hybrid 2 and Hybrid 3 combines at the 2-exocyclic amino group of the 2'-deoxyguanosine by a linker and the 2-exocyclic amino group of guanine exists in the minor groove side of the duplex. Hybrid 2 is the 2'-deoxyguanosine-pyrrolepolyamide hybrid using the 3-aminopropionyl linker, while Hybrid 3 uses the 3-aminopropyl linker. An evaluation of the DNA binding sequence selectivity was performed by analysis of T(m) values and CD spectra, using distamycin A as a contrast. Hybrid 3 has provided more excellent sequence-distinguishable ability than other hybrids and Distamycin A. Moreover, on the basis of these results, we synthesized oligonucleotides conjugated to Hybrid 4, which is stable under conditions of DNA oligonucleotide solid phase synthesis, arranged from Hybrid 3. From T(m) values and CD spectral analysis, it was found that oligonucleotides conjugating Hybrid 4 possess high recognition ability and very high binding ability for the DNA that includes the pyrrolepolyamide binding sequence.

Publication types

  • English Abstract
  • Review

MeSH terms

  • DNA
  • Drug Design*
  • Gene Expression / drug effects*
  • Nucleosides* / chemical synthesis
  • Nucleosides* / chemistry
  • Nucleosides* / pharmacology
  • Nylons* / chemical synthesis
  • Nylons* / chemistry
  • Nylons* / pharmacology
  • Oligonucleotides* / chemical synthesis
  • Oligonucleotides* / chemistry
  • Oligonucleotides* / pharmacology

Substances

  • Nucleosides
  • Nylons
  • Oligonucleotides
  • DNA