1,3-Benzodioxole Derivatives Improve the Anti-Tumor Efficiency of Arsenicals

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.

Reprogramming Energy Metabolism with Synthesized PDK Inhibitors Based on Dichloroacetate Derivatives and Targeted Delivery Systems for Enhanced Cancer Therapy

“…Then, the antitumor efficiency was determined in 4T1 syngeneic mice models. The tumor-bearing mice with the tumor size of ∼100 mm 3 were randomly divided into five groups and intravenously injected with PBS, 1f ([As] = 1.5 mg/kg, a usual dose of arsenical used in previous studies), ,− 1f ([As] = 0.15 mg/kg), LDL ([As] = 0.15 mg/kg), and HDL ([As] = 0.15 mg/kg) once a week, respectively. After treatment and observation for 2 weeks, the mice were sacrificed.…”