1,3-Benzodioxole Derivatives Improve the Anti-Tumor Efficiency of Arsenicals |
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Authors: | Xue-Min Shi Wen-Yan She Ting-Ting Liu Lian-Xun Gao Yu-Jiao Liu Yi Liu |
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Affiliation: | 1.College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, China; (X.-M.S.); (W.-Y.S.); (L.-X.G.);2.State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry, Tiangong University, Tianjin 300387, China; |
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Abstract: | Arsenicals have been widely used in the treatment of cancers such as leukemia and other tumors. However, their side effects limit their clinical application. Stiripentol, a second-line adjunctive treatment for epilepsy with a good safety profile, inhibits microsomal cytochrome-P450-family enzymes to extend the retention time of co-administration. Inspired by the metabolism of stiripentol, the 1,3-benzodioxole responsible for the inhibition and its metabolic derivatives were conjugated with arsenical precursors. The fabricated arsenicals were eliminated much slower in mice and maintained an efficient concentration in the blood for a longer time than that of the arsenical precursors. They also performed better in anti-proliferation by inhibiting the thioredoxin system to induce oxidative stress, and concomitantly to initiate apoptosis in vitro and in vivo. The fabricated arsenicals reversed the hemogram of tumor-bearing mice to normal and eliminated the tumor without causing damage to any organs, exhibiting a good design strategy and pre-clinical application for leukemia and other tumors. |
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Keywords: | organic arsenicals TrxR ROS docking 4T1 tumor stiripentol |
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