Apoptolidin
(Synonyms: Apoptolidin A) 目录号 : GC42827
An apoptosis inducer and F1FO ATPase inhibitor
Cas No.:194874-06-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >95.00%
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- SDS (Safety Data Sheet)
- Datasheet
Apoptolidin is an apoptosis inducer originally isolated from Nocardiopsis bacteria. It inhibits the mitochondrial F1FO ATPase (Ki = 4-5 µM). Apoptolidin selectively kills transformed glial cells without significantly affecting untransformed cells. It also has antibiotic and antifungal actions.
| Cas No. | 194874-06-1 | SDF | |
| 别名 | Apoptolidin A | ||
| Canonical SMILES | O[C@H]([C@](OC(/C(C)=C/C(C)=C/C(C)=C/[C@@H](C)[C@H](O[C@@](O[C@@H](C)[C@H](OC)[C@H]1O)([H])[C@H]1O)/C=C/C(C)=C/CC2)=O)([H])C[C@@H]([C@H]2O)OC)[C@](O[C@@H]3C[C@H](COC)O[C@H](O[C@@H](C)[C@@H]4O[C@@](O[C@H](C)[C@H]5O)([H])C[C@H]5OC)C[C@@]4(O)C)([C@@H]([ | ||
| 分子式 | C58H96O21 | 分子量 | 1129.4 |
| 溶解度 | DMF: Soluble,DMSO: Soluble,Ethanol: Soluble,Methanol: Soluble | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.8854 mL | 4.4271 mL | 8.8543 mL |
| 5 mM | 0.1771 mL | 0.8854 mL | 1.7709 mL |
| 10 mM | 0.0885 mL | 0.4427 mL | 0.8854 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase
Nat Chem Biol 2022 Apr;18(4):360-367.PMID:34857958DOI:10.1038/s41589-021-00900-9.
Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The Apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene-transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1 subcomplex of mitochondrial ATP synthase as the target of Apoptolidin A. Cryogenic electron microscopy (cryo-EM) of Apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence defines the mechanism of action of Apoptolidin family glycomacrolides and establishes a path to address oxidative phosphorylation-dependent cancers.
Apoptolidin: induction of apoptosis by a natural product
Angew Chem Int Ed Engl 2006 Jan 30;45(6):872-93.PMID:16404760DOI:10.1002/anie.200502698.
Apoptolidin is a natural product that selectively induces apoptosis in several cancer cell lines. Apoptosis, programmed cell death, is a biological key pathway for regulating homeostasis and morphogenesis. Apoptotic misregulations are connected with several diseases, in particular cancer. The extrinsic way to apoptosis leads through death ligands and death receptors to the activiation of the caspase cascade, which results in proteolytic degradation of the cell architecture. The intrinsic pathway transmits signals of internal cellular damage to the mitochondrion, which loses its structural integrity, and forms an apoptosome that initiates the caspase cascade. Compounds which regulate apoptosis are of high medical significance. Many natural products regulate apoptotic pathways, and Apoptolidin is one of them. The known synthetic routes to Apoptolidin are described and compared in this Review. Selected further natural products which regulate apoptosis are introduced briefly.
Apoptolidin, a selective cytotoxic agent, is an inhibitor of F0F1-ATPase
Chem Biol 2001 Jan;8(1):71-80.PMID:11182320DOI:10.1016/s1074-5521(00)00057-0.
Background: Apoptolidin is a macrolide originally identified on the basis of its ability to selectively kill E1A and E1A/E1B19K transformed rat glial cells while not killing untransformed glial cells. The goal of this study was to identify the molecular target of this newly discovered natural product. Results: Our approach to uncovering the mechanism of action of Apoptolidin utilized a combination of molecular and cell-based pharmacological assays as well as structural comparisons between Apoptolidin and other macrocyclic polyketides with known mechanism of action. Cell killing induced by Apoptolidin was independent of p53 status, inhibited by BCL-2, and dependent on the action of caspase-9. PARP was completely cleaved in the presence of 1 microM Apoptolidin within 6 h in a mouse lymphoma cell line. Together these results suggested that Apoptolidin might target a mitochondrial protein. Structural comparisons between Apoptolidin and other macrolides revealed significant similarity between the Apoptolidin aglycone and oligomycin, a known inhibitor of mitochondrial F0F1-ATP synthase. The relevance of this similarity was established by demonstrating that Apoptolidin is a potent inhibitor of the F0F1-ATPase activity in intact yeast mitochondria as well as Triton X-100-solubilized ATPase preparations. The K(i) for Apoptolidin was 4-5 microM. The selectivity of Apoptolidin in the NCI-60 cell line panel was found to correlate well with that of several known anti-fungal natural products that inhibit the eukaryotic mitochondrial F0F1-ATP synthase. Significance: Although the anti-fungal activities of macrolide inhibitors of the mitochondrial F0F1-ATP synthase such as oligomycin, ossamycin and cytovaricin are well-documented, their unusual selectivity toward certain cell types is not widely appreciated. The recent discovery of Apoptolidin, followed by the demonstration that it is an inhibitor of the mitochondrial F0F1-ATP synthase, highlights the potential relevance of these natural products as small molecules to modulate apoptotic pathways. The mechanistic basis for selective cytotoxicity of mitochondrial ATP synthase inhibitors is discussed.
Antimetastatic Activity of Apoptolidin A by Upregulation of N-Myc Downstream-Regulated Gene 1 Expression in Human Colorectal Cancer Cells
Pharmaceuticals (Basel) 2023 Mar 26;16(4):491.PMID:37111248DOI:10.3390/ph16040491.
Colorectal cancer (CRC) is one of the most prevalent tumors with high metastatic potential; consequently, finding new drug candidates that suppress tumor metastasis is essential. Apoptolidin A is a macrocyclic lactone produced by Amycolatopsis sp. DW02G. It exhibits significant cytotoxicity against several cancer cell lines, but its effects on CRC cells remain unknown. Therefore, the present study investigated the antiproliferative and antimetastatic activities of Apoptolidin A and its underlying molecular mechanisms in CRC cells. Apoptolidin A effectively inhibited CRC cell growth and colony formation. The induction of G0/G1 phase cell cycle arrest was associated with the downregulation of cyclin D1 and CDK4/6 expression. Long-term exposure to Apoptolidin A also induced apoptosis as confirmed by the downregulation and upregulation of Bcl-2 and Bax expression, respectively. Moreover, Apoptolidin A effectively upregulated the suppressed expression of N-Myc downstream-regulated gene 1 (NDRG1), a tumor suppressor gene, in a concentration-dependent manner in CRC cells. The antimetastatic potential of Apoptolidin A was also correlated with the expression of epithelial-mesenchymal transition (EMT) biomarkers, including the upregulation of E-cadherin and downregulation of N-cadherin, vimentin, snail, and MMP9 in CRC cells. These findings suggest that Apoptolidin A exerts antiproliferative and antimetastatic activities by regulating the NDRG1-activated EMT pathway in CRC cells.
An approach to the site-selective diversification of Apoptolidin A with peptide-based catalysts
J Nat Prod 2009 Oct;72(10):1864-9.PMID:19769383DOI:10.1021/np9004932.
We report the application of peptide-based catalysts to the site-selective modification of Apoptolidin A (1), an agent that displays remarkable selectivity for inducing apoptosis in E1A-transformed cell lines. Key to the approach was the development of an assay suitable for the screening of dozens of catalysts in parallel reactions that could be conducted using only microgram quantities of the starting material. Employing this assay, catalysts (e.g., 11 and ent-11) were identified that afforded unique product distributions, distinct from the product mixtures produced when a simple catalyst (N,N-dimethyl-4-aminopyridine (10)) was employed. Preparative reactions were then carried out with the preferred catalysts so that unique, homogeneous Apoptolidin analogues could be isolated and characterized. From these studies, three new Apoptolidin analogues were obtained (12-14), each differing from the other in either the location of acyl group substituents or the number of acetate groups appended to the natural product scaffold. Biological evaluation of the new Apoptolidin analogues was then conducted using growth inhibition assays based on the H292 human lung carcinoma cell line. The new analogues exhibited activities comparable to Apoptolidin A.