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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 (Δψ_m). 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.

SUBMITTER: Wang S

PROVIDER: S-EPMC9920806 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Wang Sibei S Zhang Qi Q Peng Maoqin M Xu Jing J Guo Yuanqiang Y

Molecules (Basel, Switzerland) 20230119 3

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 i ...[more]

PMID: 36770683

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Project description:Calixarene and its derivatives have extensively served as promising anti-tumor agents. Previously, we have synthesized a series of calix[n]arene polyhydroxyamine derivatives (n = 4, 6, 8) and found that 5,11,17,23-tetra-tert-butyl-25,27-bis [N-(2-hydroxyethyl)aminocarbonylmethoxyl] calix[4]arene (CLX-4) displayed significant effect toward SKOV3, A549, SW1990, HeLa, Raji, and MDA-MB-231 cancer cells. In the present work, we find a replacement of calix[4]arene bone and synthesized 19 novel structurally related dihomooxacalix[4]arene amide derivatives 4A-4S to optimize its efficacy. Their abilities to induce cytotoxicity in human lung carcinoma (A549) cells, breast cancer (MCF-7) cells, cervical cancer (HeLa) cells, hepatocellular carcinoma (HepG2) cells, as well as human umbilical vein endothelial (HUVEC) cells are evaluated in vitro. Encouraging results show that the majority of dihomooxacalix[4]arene amide derivatives are effective at inhibiting A549 cell proliferation with the corresponding IC50 ranging from 0.6 to 20.1 μM. In particular, compounds 4A, 4D, and 4L explore markedly increased potency (IC50 value is 2.0 ± 0.5 μM, 0.7 ± 0.1 μM, and 1.7 ± 0.4 μM) over the cytotoxicity profiles of control CLX-4, whose IC50 value is 2.8 ± 0.3 μM. More interestingly, 4A also demonstrates the perfect cytotoxic effect against MCF-7, HeLa, and HepG2 cells with IC50 values of 1.0 ± 0.1 μM, 0.8 ± 0.2 μM, and 2.7 ± 0.4 μM. In addition, the results proved that our synthesized 4A has much lower toxicity (41%) to normal cells at a concentration of 10 μM than that of 4D (90%). To reveal the mechanisms, the key indicators including the cell cycle and apoptosis are observed by the flow cytometry analysis in MCF-7 cells. The results demonstrate that both 4A and 4D can induce the MCF-7 cell cycle arrest in G0/G1 phase and cell apoptosis. Therefore, our finding proves that the dihomooxacalix[4]arene amide derivatives are convenient platforms for potential supramolecular anticancer agents.

Dataset Information

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

Publications

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

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