Indibulin
(Synonyms: 2-(1-(4-氯苄基)-1H-吲哚-3-基)-2-氧代-N-(吡啶-4-基)乙酰胺,ZIO 301; D 24851) 目录号 : GC36308
An inhibitor of microtubule assembly
Cas No.:204205-90-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
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Indibulin is an inhibitor of microtubule assembly.1 It destabilizes microtubules and is selective for immature neuronal and nonneuronal microtubules over mature neuronal microtubules.2 Indibulin is cytotoxic to a variety of cancer cells, including human SKOV3 ovarian, U87 glioblastoma, and AsPC-1 pancreatic cancer cells (IC50s = 36, 77, and 285 nM, respectively).1 It also induces complete tumor regression in a rat Yoshida AH13 sarcoma model when administered at a dose of 10 mg/kg without inducing systemic or neurotoxicity.
1.Bacher, G., Nickel, B., Emig, P., et al.D-24851, a novel synthetic microtubule inhibitor, exerts curative antitumoral activity in vivo, shows efficacy toward multidrug-resistant tumor cells, and lacks neurotoxicityCancer Res.61(1)392-399(2001) 2.Wienecke, A., and Bacher, G.Indibulin, a novel microtubule inhibitor, discriminates between mature neuronal and nonneuronal tubulinCancer Res.69(1)171-177(2009)
| Cas No. | 204205-90-3 | SDF | |
| 别名 | 2-(1-(4-氯苄基)-1H-吲哚-3-基)-2-氧代-N-(吡啶-4-基)乙酰胺,ZIO 301; D 24851 | ||
| Canonical SMILES | O=C(NC1=CC=NC=C1)C(C2=CN(CC3=CC=C(Cl)C=C3)C4=C2C=CC=C4)=O | ||
| 分子式 | C22H16ClN3O2 | 分子量 | 389.83 |
| 溶解度 | DMSO: 50 mg/mL (128.26 mM) | 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 | 2.5652 mL | 12.8261 mL | 25.6522 mL |
| 5 mM | 0.513 mL | 2.5652 mL | 5.1304 mL |
| 10 mM | 0.2565 mL | 1.2826 mL | 2.5652 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。
Indibulin dampens microtubule dynamics and produces synergistic antiproliferative effect with vinblastine in MCF-7 cells: Implications in cancer chemotherapy
Sci Rep 2018 Aug 17;8(1):12363.PMID:30120268DOI:10.1038/s41598-018-30376-y.
Indibulin, a synthetic inhibitor of tubulin assembly, has shown promising anticancer activity with a minimal neurotoxicity in preclinical animal studies and in Phase I clinical trials for cancer chemotherapy. Using time-lapse confocal microscopy, we show that Indibulin dampens the dynamic instability of individual microtubules in live breast cancer cells. Indibulin treatment also perturbed the localization of end-binding proteins at the growing microtubule ends in MCF-7 cells. Indibulin reduced inter-kinetochoric tension, produced aberrant spindles, activated mitotic checkpoint proteins Mad2 and BubR1, and induced mitotic arrest in MCF-7 cells. Indibulin-treated MCF-7 cells underwent apoptosis-mediated cell death. Further, the combination of Indibulin with an anticancer drug vinblastine was found to exert synergistic cytotoxic effects on MCF-7 cells. Interestingly, Indibulin displayed a stronger effect on the undifferentiated neuroblastoma (SH-SY5Y) cells than the differentiated neuronal cells. Unlike Indibulin, vinblastine and colchicine produced similar depolymerizing effects on microtubules in both differentiated and undifferentiated SH-SY5Y cells. The data indicated a possibility that Indibulin may reduce chemotherapy-induced peripheral neuropathy in cancer patients.
Indibulin, a novel microtubule inhibitor, discriminates between mature neuronal and nonneuronal tubulin
Cancer Res 2009 Jan 1;69(1):171-7.PMID:19118000DOI:10.1158/0008-5472.CAN-08-1342.
Microtubule inhibitors interfere with microtubule dynamics, causing cell cycle arrest and apoptosis. These effects are responsible for the chemotherapeutic activities of members of the taxane and Vinca alkaloid families in oncology. Unfortunately, a major side effect of the taxanes and Vinca alkaloids is the development of peripheral neuropathies. Indibulin (N-[pyridin-4-yl]-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid; D-24851; ZIO-301), a novel synthetic small molecule microtubule inhibitor, destabilizes microtubules and has antitumor activity but does not exhibit neurotoxicity in preclinical animal studies. In the present study, it has been found that Indibulin is able to discriminate between highly posttranslationally modified tubulin present in mature neuronal microtubules, and less-modified tubulin present in immature neuronal or nonneuronal microtubules. Vincristine and colchicine act on either tubulin equally well. The binding site of Indibulin on mature neuronal microtubules seems to be inaccessible due to the posttranslational modifications, a theory that is supported by the observation that Indibulin did not disrupt the integrity of highly modified microtubules present in neurites of pheochromocytoma (PC12) cells. The specificity of Indibulin for unmodified microtubules seems to be dependent on the pyridyl moiety of Indibulin because derivatives that have the pyridyl moiety replaced are not able to discriminate between highly and less-modified tubulins. The observed broad antitumor activity of Indibulin and the lack of central and peripheral nervous system toxicity in preclinical studies make it a promising candidate for development as a cancer treatment. Indibulin is currently in phase I clinical trials.
Synthesis and anti-breast cancer activity of novel Indibulin related diarylpyrrole derivatives
Daru 2019 Jun;27(1):179-189.PMID:30891679DOI:10.1007/s40199-019-00260-9.
Background: During recent years, a number of anti-tubulin agents were introduced for treatment of diverse types of cancer. Despite their potential in the treatment of cancer, drug resistance and adverse toxicity, such as peripheral neuropathy, are some of the negative effects of anti-tubulin agents. Among anti-tubulin agents, Indibulin was found to cause minimal peripheral neuropathy. Thus far, however, Indibulin has not entered clinical usage, caused in part by its poor aqueous solubility and other developmental problems in preclinical evaluation. Objectives: With respect to need for finding potent and safe anticancer agents, in our current research work, we synthesized several indibulin-related diarylpyrrole derivatives and investigated their anti-cancer activity. Methods: Cell cultur studies were perfomred using the MTT cell viability assay on the breast cancer cell lines MCF-7, T47-D, and MDA-MB231 and also NIH-3 T3 cells as representative of a normal cell line. The activity of some of the synthesized compounds for tubulin interaction was studied using colchicine binding and tubulin polymerization assays. The annexin V-FITC/PI method and flow cytometric analysis were used for studying apoptosis induction and cell cycle distribution. Results and conclusion: Two of the synthesized compounds, 4f and 4 g, showed high activity on the MDA-MB231 cell line (IC50 = 11.82 and 13.33 μM, (respectively) and low toxicity on the normal fibroblast cells (IC50 > 100 μM). All of the tested compounds were more potent on T47-D cancer cells and less toxic on NIH-3 T3 normal cells in comparison to reference compound, Indibulin. The tubulin polymerization inhibition assay and [3H]colchicine binding assay showed that the main mechanism of cell death by the potent synthesized compounds was not related to an interaction with tubulin. In the annexin V/PI staining assay, the induction of apoptosis in the MCF-7 and MDA-MB231 cell lines was observed. Cell cycle analysis illustrated an increased percentage of sub-G-1 cells in the MDA-MB231 cell line as a further indication of cell death through induction of apoptosis. Graphical abstract Novel Indibulin analogous as anti-breast cancer agents.
Synthesis and biological evaluation of indolylglyoxylamide bisphosphonates, antimitotic microtubule-targeting derivatives of Indibulin with improved aqueous solubility
Bioorg Med Chem Lett 2020 Dec 1;30(23):127635.PMID:33132173DOI:10.1016/j.bmcl.2020.127635.
Indibulin (D-24851) derivatives with bisphosphonate fragment connected to the N1 atom of imidazole ring were synthesized by alkylation of (indolyl-3)methylglyoxylates with ethylenebisphosphonate. Biological evaluation of targeted compounds 4a-d using the phenotypic sea urchin embryo assay provided evidence that replacing of p-chlorobenzene ring in Indibulin by bisphosphonate group did not eliminate antimitotic microtubule destabilizing activity. The most active molecule, tetraacid 5a, at physiological pH formed tetrasodium salt 6a with aqueous solubility value of at least 10 mg/mL. Molecule 5a was more potent in the sea urchin embryo assay than the parent Indibulin. This compound also exhibited pronounced cytotoxicity against A549 lung carcinoma and A375 melanoma cell lines.
Design, Synthesis and Anticancer Evaluation of Novel Series of Indibulin Analogues
Med Chem 2019;15(3):231-239.PMID:30324890DOI:10.2174/1573406414666181015145945.
Background: Cancer is an important cause of human death worldwide. During the last decades, many anticancer agents with anti-tubulin mechanism have been synthesized or extracted from nature and some of them also entered clinical use. Indibulin is one of the most potent tubulin polymerization inhibitors with minimal peripheral neuropathy, which is a big problem by some of the antimitotic agents such as taxanes and vinka alkaloids. With respect to this giant benefit, herein we decided to design and synthesize novel Indibulin related compounds and investigate their anticancer activity against HT-29, Caco-2 and T47-D cancerous cell lines as well as NIH-T3T as normal cell line. Objective: The aim of this study was to synthesize new anti-cancer agents and evaluates their cytotoxic activity on diverse cancerous and normal cell lines. Method: Target compounds were synthesized in multistep reaction and cytotoxic activity was investigated by MTT cell viability assay. Results: Herein, nine novel target compounds were synthesized in moderate to good yield. Some of the compounds exerted good cytotoxic activity against cancerous cell lines. Annexin V/PI staining showed that compound 4g could induce apoptosis and necrosis in HT-29 cell line. Conclusion: It is valuable to do further investigation on compound 4g which showed the highest activity against HT-29 and Caco-2 (IC50 values are 6.9 and 7 µM respectively). Also, synthesis of new derivatives of current synthesized compounds is suggested.