Structure–activity relationship study of anticancer thymidine–quinoxaline conjugates under the low radiance of long wavelength ultraviolet light for photodynamic therapy

• Significantly enhanced activity of dT-QX conjugates under UVA-1 activation.
• Thymidine dichloroquinoxaline conjugate (2Cl) as a potent anticancer agent.
• Low radiance of UVA-1 is sufficient enough to induce the full activity.
• Rapid and steady production of ROS by the 2Cl conjugate under UVA-1.

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/cm2 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.

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