Nonactin
(Synonyms: 无活菌素; Ammonium ionophore I) 目录号 : GC12090Nonactin是一种大环四内酯类抗生素和线粒体氧化磷酸化解偶联剂。
Cas No.:6833-84-7
Sample solution is provided at 25 µL, 10mM.
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Nonactin is a macrotetrolide antibiotic and mitochondrial oxidative phosphorylation uncoupler[1][2]. Nonactin inhibits recombinant human adenine nucleotide translocase (ANT) isoforms ANT1–4 with IC50 values of 4.4, 3.3, 4.7, and 3.3μM, respectively[3]. Nonactin is commonly used in studies of oxidative-phosphorylation uncoupling, ionophore mechanisms, and apoptosis in β-catenin-mutant tumors[4].
In vitro, treatment of BHK cells with Nonactin (5μg/ml; 12-14h) blocks cell-surface expression of NDV-HN and VSV-G glycoproteins without reducing their total synthesis, causes intracellular accumulation of VSV-G, inhibits syncytium formation and lowers infectious-virus yield[5]. Treatment of medullary thyroid carcinoma TT cells with Nonactin (0.12-0.5µM; 72h) reduces RET protein and mRNA level, suppresses pAKT/pmTOR signaling, induces G1 arrest, lowers cyclin D1/E, E2F1 and BCL-2, increases γH2AX and cleaved PARP, and elevates caspase-3/7 activity[6].
In vivo, Nonactin (100mg/kg/day; i.p.; 4 days) induced marked tumor regression and robust TUNEL-positive apoptosis in β-catenin-mutant HCT 116 xenograft mice without significant body-weight loss[7].
References:
[1] Pampaloni F, Mayer B, Kabat Vel-Job K, et al. A Novel Cellular Spheroid-Based Autophagy Screen Applying Live Fluorescence Microscopy Identifies Nonactin as a Strong Inducer of Autophagosomal Turnover. SLAS Discov. 2017;22(5):558-570.
[2] Martínez-Haya B, Avilés-Moreno JR, Hamad S, Elguero J. On the ionophoric selectivity of nonactin and related macrotetrolide derivatives. Phys Chem Chem Phys. 2017;19(2):1288-1297.
[3] Zhang Y, Tian D, Matsuyama H, et al. Human Adenine Nucleotide Translocase (ANT) Modulators Identified by High-Throughput Screening of Transgenic Yeast. J Biomol Screen. 2016;21(4):381-390.
[4] Hu J, Zhang J, He J. Structures, Synthesis and Biological Activities of Nonactic Acid and Its Derivatives. Curr Med Chem. 2021;28(42):8673-8691.
[5] Lee JM, Kim JG, Kim TH, et al. Nonactin hinders intracellular glycosylation in virus-infected baby hamster kidney cells. Mol Med Rep. 2010;3(1):115-119.
[6] Alqahtani T, Alsubait A, Aloumi M, et al. A novel role for nonactin: interfering with G-quadruplex in RET-driven medullary thyroid cancer. BMC Cancer. 2024;24(1):1569.
[7] Shikata Y, Kiga M, Futamura Y, et al. Mitochondrial uncoupler exerts a synthetic lethal effect against β-catenin mutant tumor cells. Cancer Sci. 2017;108(4):772-784.
Nonactin是一种大环四内酯类抗生素和线粒体氧化磷酸化解偶联剂[1][2]。Nonactin可抑制重组人腺嘌呤核苷转运酶（ANT）亚型 ANT1-4，IC50分别4.4、3.3、4.7 和 3.3μM[3]。Nonactin常用于氧化磷酸化解偶联、离子载体机制及β-catenin突变型肿瘤凋亡研究[4]。
体外实验中，用Nonactin（5μg/ml；处理 12-14h）处理BHK细胞可阻断NDV-HN和VSV-G糖蛋白的细胞表面表达，而不减少其总合成，导致VSV-G在细胞内积聚，抑制合胞体形成并降低病毒产量[5]。用Nonactin（0.12-0.5µM；72h）处理髓样甲状腺癌TT细胞可降低RET蛋白和mRNA水平，抑制pAKT/pmTOR信号通路，诱导G1期阻滞，下调cyclin D1/E、E2F1和BCL-2，增加γH2AX和cleaved PARP，并提升 caspase-3/7活性[6]。
在体内，Nonactin（100mg/kg/天；腹腔注射；4 天）在β-catenin突变型HCT 116异种移植小鼠中显著诱导肿瘤退缩和大量TUNEL阳性细胞凋亡，且未引起明显体重下降[7]。
| Cell experiment [1]: | |
Cell lines | MTC-derived TT cells |
Preparation Method | The MTC-derived TT cells were cultured in DMEM/F12 medium enriched with 15% heat-inactivated fetal bovine serum (FBS) and maintained under a humidified atmosphere with 5% CO2 at 37°C. Cells were plated at 7,500 cells per well in a 96-well plate and allowed to adhere overnight. Following this, they were exposed to various concentrations of Nonactin (0.12-0.5µM) for up to 72h. To evaluate cell viability, a solution of 0.33mg/mL MTS dye mixed with 200µg/mL phenazine methosulfate (PMS) was used. Absorbance readings were taken at 490nm. Caspase-3 activity in TT cells was evaluated utilizing the ApoAlert Caspase Fluorescent Assay kit. And cells were collected for PCR and Western blot analyses. |
Reaction Conditions | 0.12-0.5µM; 72h |
Applications | Treatment of medullary thyroid carcinoma TT cells with Nonactin reduces RET protein and mRNA level, suppresses pAKT/pmTOR signaling, lowers cyclin D1/E, E2F1 and BCL-2, increases γH2AX and cleaved PARP, and elevates caspase-3/7 activity. |
| Animal experiment [2]: | |
Animal models | BALB/cA Jcl-nu mice |
Preparation Method | Specific pathogen-free female nude mice (BALB/cA Jcl-nu) were used in this experiment. β-catenin-mutant HCT 116 cells (2×106cells/mL) were inoculated subcutaneously into the axillar region of the nude mice on Day 0. Nonactin was dissolved in 10% dimethylacetamide, 10% NIKKOL HCO60, and saline and given daily to the animals by intraperitoneal administration (100mg/kg). Tumor-bearing nude mice were randomly grouped (six mice/group), and administration of nonactin started on Day 9 to Day 12. Tumor volumes were calculated using a microgauge according to the following equations: Tumor volume (mm3)=1/2×(tumor length)×(tumor width)2. TUNEL staining of xenograft tumor tissue was performed using the FragEL DNA Fragmentation Detection Kit according to the manufacturer’s protocol. Tissue sections were viewed at 100×magnification, and images were captured with a digital camera. |
Dosage form | 100mg/kg/day; i.p.; 4 days |
Applications | Nonactin (100mg/kg/day; i.p.; 4 days) induced marked tumor regression and robust TUNEL-positive apoptosis in β-catenin-mutant HCT 116 xenograft mice without significant body-weight loss[7]. |
References: | |
| Cas No. | 6833-84-7 | SDF | |
| 别名 | 无活菌素; Ammonium ionophore I | ||
| 化学名 | (1R,2R,5R,7R,10S,11S,14S,16S,19R,20R,23R,25R,28S,29S,32S,34S)-2,5,11,14,20,23,29,32-octamethyl-4,13,22,31,37,38,39,40-octaoxapentacyclo[32.2.1.17,10.116,19.125,28]tetracontane-3,12,21,30-tetrone | ||
| Canonical SMILES | O=C([C@H](C)[C@@H]1O[C@H]2CC1)O[C@H](C)C[C@@H]3O[C@H]([C@H](C)C(O[C@@H](C)C[C@H]4O[C@@H]([C@@H](C)C(O[C@H](C)C[C@@H]5O[C@H]([C@H](C)C(O[C@@H](C)C2)=O)CC5)=O)CC4)=O)CC3 | ||
| 分子式 | C40H64O12 | 分子量 | 736.94 |
| 溶解度 | 1mg/mL in ethanol, 0.25mg/mL in DMSO, 10mg/mL in DMF | 储存条件 | Desiccate at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.357 mL | 6.7848 mL | 13.5696 mL |
| 5 mM | 271.4 μL | 1.357 mL | 2.7139 mL |
| 10 mM | 135.7 μL | 678.5 μL | 1.357 mL |
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