TY - JOUR
T1 - DNA cleavage at the AP site via β-elimination mediated by the AP site-binding ligands
AU - Abe, Yukiko S.
AU - Sasaki, Shigeki
N1 - Funding Information:
This work was supported by a Grant-in-Aid for Scientific Research (B) (Grant Number 15H04633 for S. S.) and a Grant-in-Aid for Young Scientists (B) (Grant Number 26860079 for Y. A.) from the Japan Society for Promotion of Science ( JSPS ).
Publisher Copyright:
© 2016 Elsevier Ltd. All rights reserved.
PY - 2016/2/15
Y1 - 2016/2/15
N2 - DNA is continuously damaged by endogenous and exogenous factors such as oxidation and alkylation. In the base excision repair pathway, the damaged nucleobases are removed by DNA N-glycosylase to form the abasic sites (AP sites). The alkylating antitumor agent exhibits cytotoxicity through the formation of the AP site. Therefore blockage or modulation of the AP site repair pathway may enhance the antitumor efficacy of DNA alkylating agents. In this study, we have examined the effects of the nucleobase-polyamine conjugated ligands (G-, A-, C- and T-ligands) on the cleavage of the AP site. The G- and A-ligands cleaved DNA at the AP site by promoting β-elimination in a non-selective manner by the G-ligand, and in a selective manner for the opposing dT by the A-ligand. These results suggest that the nucleobase-polyamine conjugate ligands may have the potential for enhancement of the cytotoxicities of the AP site.
AB - DNA is continuously damaged by endogenous and exogenous factors such as oxidation and alkylation. In the base excision repair pathway, the damaged nucleobases are removed by DNA N-glycosylase to form the abasic sites (AP sites). The alkylating antitumor agent exhibits cytotoxicity through the formation of the AP site. Therefore blockage or modulation of the AP site repair pathway may enhance the antitumor efficacy of DNA alkylating agents. In this study, we have examined the effects of the nucleobase-polyamine conjugated ligands (G-, A-, C- and T-ligands) on the cleavage of the AP site. The G- and A-ligands cleaved DNA at the AP site by promoting β-elimination in a non-selective manner by the G-ligand, and in a selective manner for the opposing dT by the A-ligand. These results suggest that the nucleobase-polyamine conjugate ligands may have the potential for enhancement of the cytotoxicities of the AP site.
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U2 - 10.1016/j.bmc.2016.01.016
DO - 10.1016/j.bmc.2016.01.016
M3 - Article
C2 - 26777298
AN - SCOPUS:84956802489
SN - 0968-0896
VL - 24
SP - 910
EP - 914
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 4
ER -