Electrochemical detection of the oxidative damage of a potential pyrimido[5,4-g]pteridine-derived antitumor agent toward DNA

In this work, we design and synthesize 2,2 ' -(7,9-dimethyl-2,4,6,8-tetraoxo-6,7,8,9-tetrahydropyrimido[5,4-g]pteridine-1,3(2H,4H)-diyl)bis(N,N-bis(2-chloroethyl)acetamide) (PT-MCA) as a novel DNA intercalator and potential antitumor agent. Electrochemical analysis reveals the redox process of PT-MCA on the electrode surface. The bioelectrochemical sensors are obtained by modifying the surface of GCE with calf thymus DNA (ctDNA), poly (dG), poly (dA), and G-quadruplex, respectively. The DNA oxidative damage induced by PT-MCA is investigated by comparing the peak intensity change of dGuo and dAdo and monitoring the peaks of the oxidation products of guanine and/or adenine (8-oxoGua and/or 2,8-oxoAde). UV-vis absorption and fluorescence spectra and gel electrophoresis are further employed to understand the intercalation of PT-MCA into DNA base pairs. Moreover, PT-MCA is proved to exhibit stronger anti-proliferation activity than mitoxantrone against both 4T1 and B16-F10 cancer cells. At last, the oxidative damage of PT-MCA toward ctDNA is not interfered by the coexistence of ions and also can be detected in real serums.

Automated summary

In this study, a novel DNA intercalator, PT-MCA, was designed and synthesized as a potential antitumor agent. The redox process of PT-MCA on the electrode surface was investigated through electrochemical analysis. Bioelectrochemical sensors were fabricated by modifying the surface of GCE with different DNA structures, and the oxidative damage of DNA induced by PT-MCA was characterized using various analytical techniques. Moreover, PT-MCA exhibited stronger anti-proliferation activity than mitoxantrone against cancer cells and could be detected in real serums without interference from ions.