Synthesis and binding properties of new selective ligands for the nucleobase opposite the AP site

Yukiko Abe, Osamu Nakagawa, Rie Yamaguchi, Shigeki Sasaki

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

DNA is continuously damaged by endogenous and exogenous factors such as oxidative stress or DNA alkylating agents. These damaged nucleobases are removed by DNA N-glycosylase and form apurinic/apyrimidinic sites (AP sites) as intermediates in the base excision repair (BER) pathway. AP sites are also representative DNA damages formed by spontaneous hydrolysis. The AP sites block DNA polymerase and a mismatch nucleobase is inserted opposite the AP sites by polymerization to cause acute toxicities and mutations. Thus, AP site specific compounds have attracted much attention for therapeutic and diagnostic purposes. In this study, we have developed nucleobase-polyamine conjugates as the AP site binding ligand by expecting that the nucleobase part would play a role in the specific recognition of the nucleobase opposite the AP site by the Watson-Crick base pair formation and that the polyamine part should contribute to the access of the ligand to the AP site by a non-specific interaction to the DNA phosphate backbone. The nucleobase conjugated with 3,3′-diaminodipropylamine (A-ligand, G-ligand, C-ligand, T-ligand and U-ligand) showed a specific stabilization of the duplex containing the AP site depending on the complementary combination with the nucleobase opposite the AP site; that is A-ligand to T, G-ligand to C, C-ligand to G, T- and U-ligand to A. The thermodynamic binding parameters clearly indicated that the specific stabilization is due to specific binding of the ligands to the complementary AP site. These results have suggested that the complementary base pairs of the Watson-Crick type are formed at the AP site.

Original languageEnglish
Pages (from-to)3470-3479
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number11
DOIs
Publication statusPublished - Jun 1 2012

Fingerprint

Ligands
DNA
Polyamines
Base Pairing
Stabilization
DNA Glycosylases
Oxidative stress
Alkylating Agents
DNA-Directed DNA Polymerase
Thermodynamics
DNA Repair
Polymerization
DNA Damage
Toxicity
Hydrolysis
Oxidative Stress
Repair
Phosphates
Binding Sites
Mutation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Synthesis and binding properties of new selective ligands for the nucleobase opposite the AP site. / Abe, Yukiko; Nakagawa, Osamu; Yamaguchi, Rie; Sasaki, Shigeki.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 11, 01.06.2012, p. 3470-3479.

Research output: Contribution to journalArticle

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