Taccalonolide AJ
(Synonyms: 根薯酮内酯AJ) 目录号 : GC37716
Taccalonolide AJ 是一种具有细胞微管稳定活性的半合成化合物。Taccalonolide AJ 对癌细胞具有高效的抗增殖活性，对 HeLa 细胞作用的 IC50 值为 4.2 nM。
Cas No.:1349904-82-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Taccalonolide AJ is a semi-synthesis compound with cellular microtubule stabilizing activity. Taccalonolide AJ exhibits high potency antiproliferative activity against cancer cells, with an IC50 of 4.2 nM for HeLa cells[1]. microtubule[1]
[1]. Li J, et al. Potent taccalonolides, AF and AJ, inform significant structure-activity relationships and tubulin as the binding site of these microtubule stabilizers. J Am Chem Soc. 2011 Nov 30;133(47):19064-7.
| Cas No. | 1349904-82-0 | SDF | |
| 别名 | 根薯酮内酯AJ | ||
| Canonical SMILES | C[C@]1([C@@]2(O)C)[C@]3(OC2=O)[C@H]([C@@H](C)[C@@]4([H])[C@@]1([H])[C@@H]([C@]5([H])[C@@]4([C@H]([C@@H](OC(C)=O)[C@@]6([H])[C@@]5([H])[C@H](C([C@]7([H])[C@@]6([C@H]([C@@H](O8)[C@@H]8C7)OC(C)=O)C)=O)O)OC(C)=O)C)O)O3 | ||
| 分子式 | C34H44O14 | 分子量 | 676.7 |
| 溶解度 | Soluble in DMSO | 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 | 1.4778 mL | 7.3888 mL | 14.7776 mL |
| 5 mM | 0.2956 mL | 1.4778 mL | 2.9555 mL |
| 10 mM | 0.1478 mL | 0.7389 mL | 1.4778 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % 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。
Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma
Molecules 2020 Nov 27;25(23):5586.PMID:33261151DOI:10.3390/molecules25235586.
Background: Microtubule-targeted drugs are the most effective drugs for adult patients with certain solid tumors. Taccalonolide AJ (AJ) can stabilize tubulin polymerization by covalently binding to β-tubulin, which enables it to play a role in the treatment of tumors. However, its clinical applications are largely limited by low water solubility, chemical instability in water, and a narrow therapeutic window. Clear-cell renal-cell carcinoma (cc RCC) accounts for approximately 70% of RCC cases and is prone to resistance to particularly targeted therapy drugs. Methods: we prepared a water-soluble cyclodextrin-based carrier to serve as an effective treatment for cc RCC. Results: Compared with AJ, taccalonolide AJ-hydroxypropyl-β-cyclodextrin (AJ-HP-β-CD) exhibited superior selectivity and activity toward the cc RCC cell line 786-O vs. normal kidney cells by inducing apoptosis and cell cycle arrest and inhibiting migration and invasion of tumor cells in vitro. According to acute toxicity testing, the maximum tolerated dose (MTD) of AJ-HP-β-CD was 10.71 mg/kg, which was 20 times greater than that of AJ. Assessment of weight changes showed that mouse body weight recovered over 7-8 days, and the toxicity could be greatly reduced by adjusting the injections from once every three days to once per week. In addition, we inoculated 786-O cells to generate xenografted mice to evaluate the anti-tumor activity of AJ-HP-β-CD in vivo and found that AJ-HP-β-CD had a better tumor inhibitory effect than that of docetaxel and sunitinib in terms of tumor growth and endpoint tumor weight. These results indicated that cyclodextrin inclusion greatly increased the anti-tumor therapeutic window of AJ. Conclusions: the AJ-HP-β-CD complex developed in this study may prove to be a novel tubulin stabilizer for the treatment of cc RCC. In addition, this drug delivery system may broaden the horizon in the translational study of other chemotherapeutic drugs.
Taccalonolide microtubule stabilizers
Bioorg Med Chem 2014 Sep 15;22(18):5091-6.PMID:24491636DOI:10.1016/j.bmc.2014.01.012.
This review focuses on a relatively new class of microtubule stabilizers, the taccalonolides. The taccalonolides are highly oxygenated pentacyclic steroids isolated from plants of the genus Tacca. Originally identified in a cell-based phenotypic screen, the taccalonolides have many properties similar to other microtubule stabilizers. They increase the density of interphase microtubules, causing microtubule bundling, and form abnormal multi-polar mitotic spindles leading to mitotic arrest and, ultimately, apoptosis. However, the taccalonolides differ from other microtubule stabilizers in that they retain efficacy in taxane resistant cell lines and in vivo models. Binding studies with the newly identified, potent Taccalonolide AJ demonstrated covalent binding to β-tubulin at or near the luminal and/or pore taxane binding site(s) which stabilizes microtubule protofilaments in a unique manner as compared to other microtubule stabilizers. The isolation and semi-synthesis of 21 taccalonolides helped to identify key structure activity relationships and the importance of multiple regions across the taccalonolide skeleton for optimal biological potency.
Mechanism of microtubule stabilization by Taccalonolide AJ
Nat Commun 2017 Jun 6;8:15787.PMID:28585532DOI:10.1038/ncomms15787.
As a major component of the cytoskeleton, microtubules consist of αβ-tubulin heterodimers and have been recognized as attractive targets for cancer chemotherapy. Microtubule-stabilizing agents (MSAs) promote polymerization of tubulin and stabilize the polymer, preventing depolymerization. The molecular mechanisms by which MSAs stabilize microtubules remain elusive. Here we report a 2.05 Å crystal structure of tubulin complexed with Taccalonolide AJ, a newly identified taxane-site MSA. Taccalonolide AJ covalently binds to β-tubulin D226. On AJ binding, the M-loop undergoes a conformational shift to facilitate tubulin polymerization. In this tubulin-AJ complex, the E-site of tubulin is occupied by GTP rather than GDP. Biochemical analyses confirm that AJ inhibits the hydrolysis of the E-site GTP. Thus, we propose that the β-tubulin E-site is locked into a GTP-preferred status by AJ binding. Our results provide experimental evidence for the connection between MSA binding and tubulin nucleotide state, and will help design new MSAs to overcome taxane resistance.
Taccalonolide C-6 Analogues, Including Paclitaxel Hybrids, Demonstrate Improved Microtubule Polymerizing Activities
J Nat Prod 2021 Jun 25;84(6):1799-1805.PMID:34110822DOI:10.1021/acs.jnatprod.1c00211.
The C-22,23-epoxy taccalonolides are microtubule stabilizers that bind covalently to β-tubulin with a high degree of specificity. We semisynthesized and performed biochemical and cellular evaluations on 20 taccalonolide analogues designed to improve target engagement. Most notably, modification of C-6 on the taccalonolide backbone with the C-13 N-acyl-β-phenylisoserine side chain of paclitaxel provided compounds with 10-fold improved potency for biochemical tubulin polymerization as compared to that of the unmodified epoxy Taccalonolide AJ. Covalent docking demonstrated that the C-13 paclitaxel side chain occupied a binding pocket adjacent to the core taccalonolide pocket near the M-loop of β-tubulin. Although paclitaxel-taccalonolide hybrids demonstrated improved in vitro biochemical potency, they retained features of the taccalonolide chemotype, including a lag in tubulin polymerization and high degree of cellular persistence after drug washout associated with covalent binding. Together, these data demonstrate that C-6 modifications can improve the target engagement of this covalent class of microtubule drugs without substantively changing their mechanism of action.
Pharmacokinetic Analysis and in Vivo Antitumor Efficacy of Taccalonolides AF and AJ
J Nat Prod 2017 Feb 24;80(2):409-414.PMID:28112516DOI:10.1021/acs.jnatprod.6b00944.
The taccalonolides are microtubule stabilizers that covalently bind tubulin and circumvent clinically relevant forms of resistance to other drugs of this class. Efforts are under way to identify a taccalonolide with optimal properties for clinical development. The structurally similar taccalonolides AF and AJ have comparable microtubule-stabilizing activities in vitro, but taccalonolide AF has excellent in vivo antitumor efficacy when administered systemically, while Taccalonolide AJ does not elicit this activity even at maximum tolerated dose. The hypothesis that pharmacokinetic differences underlie the differential efficacies of taccalonolides AF and AJ was tested. The effects of serum on their in vivo potency, metabolism by human liver microsomes and in vivo pharmacokinetic properties were evaluated. Taccalonolides AF and AJ were found to have elimination half-lives of 44 and 8.1 min, respectively. Furthermore, Taccalonolide AJ was found to have excellent and highly persistent antitumor efficacy when administered directly to the tumor, suggesting that the lack of antitumor efficacy seen with systemic administration of AJ is likely due to its short half-life in vivo. These results help define why some, but not all, taccalonolides inhibit the growth of tumors at systemically tolerable doses and prompt studies to further improve their pharmacokinetic profile and antitumor efficacy.