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Abstract
Background/aim: Improvement of the efficacy of radiotherapy for lung cancer and glioblastoma is urgently needed.

Materials and methods: We synthesized several novel DNA methyltransferase inhibitors and evaluated their potentials as possible radiosensitizers. Eleven non-nucleoside compounds were synthesized and evaluated along with one known compound using human lung cancer (A549) and glioblastoma (U373MG) cells. Cytotoxicity and radiosensitizing effects were evaluated using clonogenic assay. Sensitizer enhancement ratios at a survival fraction of 0.5 were calculated, and statistical analysis was performed using the ratio paired t-test. The inhibitory effects of three selected compounds on the activity of DNA methyltransferase 1 (DNMT1) and the pharmacokinetic profiles were analyzed.

Results: All twelve compounds demonstrated various levels of cytotoxicity. Of the twelve compounds, eleven and eight compounds radiosensitized A549 and U373MG cells, respectively, with at least marginal significance (p<0.10). The sensitizer enhancement ratios in A549 and U373MG ranged 1.166-2.537 and 1.083-1.743 among compounds with radiosensitizing effects, respectively. The three selected compounds inhibited DNMT1 activity by 26.5-78.5%. Elimination half-lives ranged from 0.3 to 1.3 h.

Conclusion: Novel DNA methyltransferase inhibitors with significant radiosensitizing capacity and improved biostability were synthesized. These materials will serve as a basis for the development of novel radiosensitizers.

Affiliations

Chan Woo Wee  1   2 , Jin Ho Kim  2   3   4 , Hak Jae Kim  2   3   4 , Hyun-Cheol Kang  2   3   4 , Soo Youn Suh  3 , Beom Soo Shin  5 , Eunsook Ma  6 , Il Han Kim  7   3   4
1 Department of Radiation Oncology, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea.
2 Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea.
3 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
4 Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
5 School of Pharmacy, Sungkyunkwan University, Seoul, Republic of Korea.
6 College of Pharmacy, Catholic University of Daegu, Gyeongsan, Republic of Korea ihkim@snu.ac.kr masook@cu.ac.kr.
7 Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea; ihkim@snu.ac.kr masook@cu.ac.kr.