Development of selective binding and cleavage ligands for the AP sites

2016 Fiscal Year Final Research Report

• Project/Area Number: 26860079
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Kyushu University
• Principal Investigator: Abe Yukiko 九州大学, 薬学研究院, 助教 (40586856)
• Project Period (FY): 2015-03-01 – 2017-03-31
• Keywords: b-脱離 / 抗がん作用増強

Outline of Final Research Achievements

DNA is continuously damaged by endogenous and exogenous factors. In the base excision repair pathway, the damaged nucleobases are removed by DNA N-glycosylase to form AP sites. The AP site is representative DNA damage and the alkylating antitumor agents exhibit 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. We studied the effects of nucleobase-polyamine conjugates (G-, A-ligands), which specifically bind and cleave at the AP site, on the potentiation of the cytotoxicities by the alkylating agents. In the combined application of the ligand and DNA alkylating agents MMS, the G- and A-ligands showed the potential of the enhancement of antitumor efficacy. Therefore we designed and synthesized the new ligand having the high affinity and cleavage activity to AP sites.The new ligand showed the affinity to the AP sites but have only a modest ceavage activity.

Free Research Field

有機化学