Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone

Abstract

α-Mangostin, a natural xanthone, was found to have anticancer effects, but these effects are not sufficient to be effective. To increase anticancer potential and selectivity, a triphenylphosphonium cation moiety (TPP) was introduced to α-mangostin to specifically target cancer cell mitochondria. Compared to the parent compound, the cytotoxicity of the synthesized compound 1b increased by one order of magnitude. Mechanistic analysis revealed that the anti-tumor effects were involved in the mitochondrial apoptotic pathway by prompting apoptosis and arresting the cell cycle at the G0/G1 phase, increasing the production of reactive oxygen species (ROS), and reducing mitochondrial membrane potential (Δψm). More notably, the antitumor activity of compound 1b was further confirmed by zebrafish models, which remarkably inhibited cancer cell proliferation and migration, as well as zebrafish angiogenesis. Taken together, our results for the first time indicated that TPP-linked 1b could lead to the development of new mitochondrion-targeting antitumor agents.

Assessing causal associations of bile acids with obesity indicators: A Mendelian randomization study

“…[41,42] GLCA is the product of glycine coupling to LCA, in which the carboxylate group of LCA combines with glycine to form bile salts, [41,43,44] which are allowed to dissolve lipids in the small intestine, increasing the lipid surface area to be more easily absorbed, and thus lipid reduction affects obesity. [43–48] Following oral administration of GLCA to rats, a swift reduction in phospholipid and cholesterol secretion was observed, reaching 25% and 50% of their initial levels, respectively, as reported by Kuipers et al [49]…”

“…[41,42] GLCA is the product of glycine coupling to LCA, in which the carboxylate group of LCA combines with glycine to form bile salts, [41,43,44] which are allowed to dissolve lipids in the small intestine, increasing the lipid surface area to be more easily absorbed, and thus lipid reduction affects obesity. [43][44][45][46][47][48] Following oral administration of GLCA to rats, a swift reduction in phospholipid and cholesterol secretion was observed, reaching 25% and 50% of their initial levels, respectively, as reported by Kuipers et al [49] The transportation of bile phospholipids to the canalicular membrane occurs via a calcium-dependent microtubulemediated vesicle pathway. [50,51] A review of the literature shows that cells are able to maintain low concentrations of intracellular free calcium due to the efficient operation of calcium pumps located in the plasma membrane and mitochondria.…”

“…[54] LCA carboxylate group in GLCA forms bile salts with glycine, which cause toxic damage to mitochondria, leading to disruption of the intracellular calcium balance. [44,45,54–56]…”

“…[54] LCA carboxylate group in GLCA forms bile salts with glycine, which cause toxic damage to mitochondria, leading to disruption of the intracellular calcium balance. [44,45,[54][55][56] Furthermore, most lipids are hydrolyzed in the small intestine and then proceed to the large intestine after gastric preprocessing, where they are influenced by the gut microbiota for lipid utilization. [32,57,58] The Bacteroidetes and Firmicutes phyla, which dominate the human gut, play a pivotal role in regulating inflammation, obesity, and insulin sensitivity.…”