Investigation Of The Liver Cancer Chemotherapeatic Agent DT-QX Analogs And Their Activity Under UVA Irradiation

There have been great challenges in the chemotherapy for liver cancer due to few anticancer drugs avaliable, poor survival rate, severe side effects and other problems. The development of safe and effective anti-cancer drugs has been a hot area in drug development. d T-QX is a thymidine-quinoxalin conjugate that selectively kills hepatoma cells and has low activity in normal cells. However, the challenge remains due to the tumor heterogeneityits in the clinical seating. Recently, photodynamic therapy has been widely used in the treatment of various types of tumors. PDT can selectively kill the tumor by physically selecting the tumor area with minimal damage of the normal tissue. This research is aim to investigate the potential to enhance d T-QX activity by structure modification with UVA irradiation for PDT.The main contents of this thesis are:(1) Investigation of thymidine-conjugate analogs: Based on the chemical structure of d T-QX, we replaced the active quinoxalin moiety with a sunitinib derivative. In addition, halogenated quinoxalin conjugates included fluoride, bromide anologs were also synthesized, and their biological activity were assessed.(2) Biological activity of d T-QX analogs under UVA radiation for PDT: We found that under the UVA radiation, the anti-tumor activity of d T-QX was significantly enhanced. The EC50 value on hepatoma cell Bel-7402 decreased from 50 μmol/L to below 1 μmol/L, and halogen-substituted compound 2Br has the highest anti-tumor activity. We further confirmed that d T-QX generated ROS extensively under UVA radiation. In the subcutaneous tumor model study, PDT treatment group has delayed tumor growth as compared with the control group.