title: Structure-activity relationship study of anticancer thymidine-quinoxaline conjugates under the low radiance of long wavelength ultraviolet light for photodynamic therapy.
abstract: Thymidine quinoxaline conjugate (dT-QX) is a thymidine analog with selective cytotoxicity against different cancer cells. In this study, the structure activity relationship study of dT-QX analogs was carried out under the low radiance of black fluorescent (UVA-1) light. Significantly enhanced cytotoxicity was observed under UVA-1 activation among analogs containing both thymidine and quinoxaline moieties with different length of the linker, stereochemical configuration and halogenated substituents. Among these analogs, the thymidine dichloroquinoxaline conjugate exhibited potent activity under UVA-1 activation as the best candidate with EC50 at 0.67 μM and 1.3 μM against liver and pancreatic cancer cells, respectively. In contrast, the replacement of thymidine moiety with a galactosyl residue or the replacement of quinoxaline moiety with a fluorescent pyrenyl residue or a simplified diketone structure resulted in the full loss of activity. Furthermore, it was revealed that the low radiance of UVA-1 at 3 mW/cm(2) for 20 min was sufficient enough to induce the full cytotoxicity of thymidine dichloroquinoxaline conjugate and that the cytotoxic mechanism was achieved through a rapid and steady production of reactive oxygen species.
authors.affiliation: Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Dejun
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Huaming
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address: qibingzhou@hust.edu.cn.
authors.forename: Qibing
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D010778:Photochemotherapy / Q000379:methods*; D011810:Quinoxalines / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives / Q000737:chemistry; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D013936:Thymidine
keywords: Anticancer agents; Quinoxaline conjugates; Reactive oxygen species; Thymidine analogs; UVA-1 activation