Guo Fei-Fei, Li Tong, Mu Xi-Ping, Zhang Xue, Xu Zhi-Hao, Sun Ping, Yu Ri-Lei, Xia Ya-Mu, Gao Wei-Wei
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, People's Republic of China.
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China.
Anal Bioanal Chem. 2023 May;415(12):2249-2260. doi: 10.1007/s00216-023-04643-5. Epub 2023 Mar 15.
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.
在本工作中，我们设计并合成了2,2'-(7,9-二甲基-2,4,6,8-四氧代-6,7,8,9-四氢嘧啶并[5,4-g]蝶啶-1,3(2H,4H)-二亚基)双(N,N-双(2-氯乙基)乙酰胺)(PT-MCA)作为一种新型的DNA嵌入剂和潜在的抗肿瘤药物。电化学分析揭示了PT-MCA在电极表面的氧化还原过程。分别用小牛胸腺DNA(ctDNA)、聚(dG)、聚(dA)和G-四链体修饰玻碳电极(GCE)表面，制备了生物电化学传感器。通过比较dGuo和dAdo的峰强度变化以及监测鸟嘌呤和/或腺嘌呤氧化产物(8-氧代鸟嘌呤和/或2,8-氧代腺嘌呤)的峰，研究了PT-MCA诱导的DNA氧化损伤。进一步利用紫外-可见吸收光谱、荧光光谱和凝胶电泳来了解PT-MCA插入DNA碱基对的情况。此外，已证明PT-MCA对4T1和B16-F10癌细胞均表现出比米托蒽醌更强的抗增殖活性。最后，PT-MCA对ctDNA的氧化损伤不受离子共存的干扰，并且可以在真实血清中检测到。
