Mitochondria-Targeted Triphenylphosphonium Conjugated C-3 Modified Betulin: Synthesis,Antitumor Properties and Mechanism of Action |
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Authors: | Geng Xu Xiaojia Xu Jiansong Liu Qi Jia Dr Changhong Ke Hanyuan Zhang Chao Xu E Ou Prof Wen Tan Prof Yu Zhao |
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Affiliation: | School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006 China |
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Abstract: | A series of mitochondria-targeted triphenylphosphonium conjugated C-3 modified betulin were synthesized and evaluated against tumor cells. As a result, a new derivative 13 i , the conjugate of 3-O-(3′-acetylphenylacetate)-betulin with triphenylphosphonium, was identified as the one with the best anti-tumor effect. Conjugate 13 i significantly inhibited HCT116 cells with IC50 at 0.66 μM. While betulin, C-3 modified betulin, and the triphenylphosphonium moiety showed no inhibition of HCT116 cell proliferation at 20 μM. More importantly, 13 i exhibited a more cytotoxic effect against the tumor cell HCT116 than normal cell NCM460. Mode of action studies demonstrated that 13 i induced the G2/M phase cell cycle arrest and apoptosis in HCT116 cells through the mitochondrial pathway. Structure-activity relationship analysis revealed that integration of triphenylphosphonium moiety into the C-28 of betulin can greatly improve cytotoxicity. Appropriate modification on C-3 of the conjugate would improve the selectivity. |
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Keywords: | antiproliferation betulin conjugation drug discovery mitochondria structure-activity relationship triphenylphosphonium |
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