Mitochondria‐Targeted Triphenylphosphonium Conjugated C‐3 Modified Betulin: Synthesis, Antitumor Properties and Mechanism of Action

A series of mitochondria-targeted triphenylphosphonium conjugated C-3 modified betulin were synthesized and evaluated against tumor cells. As a result, a new derivative 13i, the conjugate of 3-O-(3'-acetylphenylacetate)-betulin with triphenylphosphonium, was identified as the one with the best anti-tumor effect. Conjugate 13i significantly inhibited HCT116 cells with IC 50 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, 13i exhibited a more cytotoxic effect against the tumor cell HCT116 than normal cell NCM460. Mode of action studies demonstrated that 13i induced the G2/M phase cell cycle arrest and apoptosis in HCT116 cell 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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