箭根薯酮内酯B | 108885-69-4

• 物质功能分类: 生物化工 - 提取物 - 植物提取物
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 箭根薯酮内酯B
• 中文别名: 根薯酮内酯B
• 英文名称: taccalonolide B
• 英文别名: [(1S,2S,3R,5S,7S,9S,10R,11R,12S,13S,14R,15R,16S,17S,22S,23S,24R,25R)-10,14-diacetyloxy-3,22,25-trihydroxy-11,15,17,22,23-pentamethyl-4,21-dioxo-8,20-dioxaheptacyclo[13.10.0.02,12.05,11.07,9.016,24.019,23]pentacos-18-en-13-yl] acetate
• CAS: 108885-69-4
• 化学式: C₃₄H₄₄O₁₃
• 分子量: 660.716
• InChiKey: FFQOXBQSZPYHSA-MPOUNFKCSA-N

物化性质

• 密度：
  1.43±0.1 g/cm3 (20 ºC 760 Torr)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  47
• 可旋转键数：
  6
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  196
• 氢给体数：
  3
• 氢受体数：
  13

制备方法与用途

生物活性

Taccalonolide B 是从 Tacca plantaginea 中分离得到的微管稳定剂，具有抗肿瘤活性。它在体外对过表达 p 糖蛋白 (Pgp) 和多药耐药蛋白 (MRP7) 的细胞系表现出显著抑制作用，并且能够抑制 SK-OV-3 细胞生长，其 IC50 值为 208 nM。

靶点

微管

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反应信息

• 作为反应物：
  描述：

  箭根薯酮内酯B 在 二甲基二环氧乙烷 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 箭根薯酮内酯AJ
  参考文献：
  名称：

  Potent Taccalonolides, AF and AJ, Inform Significant Structure–Activity Relationships and Tubulin as the Binding Site of These Microtubule Stabilizers

  摘要：

  The taccalonolides are a class of microtubule stabilizing agents isolated from plants of the genus Tacca. In efforts to define their structure activity relationships, we isolated five new taccalonolides, AC-AF and H2, from one fraction of an ethanol extract of Tacca plantaginea. The structures were elucidated using a combination of spectroscopic methods, including 1D and 2D NMR and HR-ESI-MS. Taccalonolide AJ, an epoxidation product of taccalonolide B, was generated by semisynthesis. Five of these taccalonolides demonstrated cellular microtubule-stabilizing activities and antiproliferative actions against cancer cells, with taccalonolide AJ exhibiting the highest potency with an IC50 value of 4.2 nM. The range of potencies of these compounds, from 4.2 nM to >50 mu M, for the first time provides the opportunity to identify specific structural moieties crucial for potent biological activities as well as those that impede optimal cellular effects. In mechanistic assays, taccalonolides AF and AJ stimulated the polymerization of purified tubulin, an activity that had not previously been observed for taccalonolides A and B, providing the first evidence that this class of microtubule stabilizers can interact directly with tubulin/microtubules. Taccalonolides AF and AJ were able to enhance tubulin polymerization to the same extent as paclitaxel but exhibited a distinct kinetic profile, suggesting a distinct binding mode or the possibility of a new binding site. The potencies of taccalonolides AF and AJ and their direct interaction with tubulin, together with the previous excellent in vivo antitumor activity of this class, reveal the potential of the taccalonolides as new anticancer agents.

  DOI：

  10.1021/ja209045k
• 作为产物：
  描述：

  箭根薯酮内酯A 在 水 、 碳酸氢钠 作用下， 以 甲醇 为溶剂， 以80%的产率得到箭根薯酮内酯B
  参考文献：
  名称：

  使用半合成生成的替卡洛洛利微管稳定剂定义了C-7或C-15处的单酰氧基部分以及C-7和C-25处的二取代的影响

  摘要：

  塔卡洛洛尼酯是一类独特的从Tacca spp分离得到的微管稳定剂。具有抗药性肿瘤的功效。我们以前的研究表明，与带有C-15羟基的AJ相比，C-15乙酰氧基他克洛奈德（AF）具有更好的体内抗肿瘤功效。为了进一步改善这类化合物的体内功效，我们半合成和测试了28种新的塔克拉波内酯的生物活性，这些新化合物在C-7或C-15处具有单取代基，在C-7和C-25处具有取代基。从甲酸到蒽醌-2-羰基氯的取代基种类繁多。所得具有多种C-7 / C-15 / C-25修饰的他卡洛洛内酯类似物显示出IC 50值从2.4 nM到> 20μM，可进行广泛的体外结构活性评估。由于C-7或C-15处取代基的水解，无论大小或空间体积如何，这种半合成策略均不能提供具有改善的治疗窗口的他克洛奈德。然而，当在肿瘤内给药时，在抗药性异种移植模型中，两个最有效的新他克洛内酯在C-7或C-15处具有异戊酸酯修饰，表现出有效且高度持久

  DOI：

  10.1021/acs.jnatprod.7b00967

文献信息

• [EN] NEW TECHNOLOGY TO CONJUGATE THE TACCALONOLIDE MICROTUBULE STABILIZERS WITH LINKERS/PAYLOADS<br/>[FR] NOUVELLE TECHNOLOGIE POUR CONJUGUER LES STABILISATEURS TACCALONOLIDES DE MICROTUBULES AVEC DES LIEURS/CHARGES UTILES
  申请人：DU LIN

  公开号：WO2020185610A1

  公开（公告）日：2020-09-17

  The present disclosure is concerned with taccalonolide analogs and conjugated taccalonolide analogs useful as cellular probes and in the treatment of, for example, hyperproliferative disorders such as cardiovascular diseases and cancer. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  本公开涉及可用作细胞探针和用于治疗高增殖性疾病，如心血管疾病和癌症的塔卡龙内酯类似物和共轭塔卡龙内酯类似物。本摘要旨在作为在特定领域搜索的扫描工具，并不意味着对本发明的限制。
• Elucidating target specificity of the taccalonolide covalent microtubule stabilizers employing a combinatorial chemical approach
  作者：Lin Du、Samantha S. Yee、Karthik Ramachandran、April L. Risinger

  DOI：10.1038/s41467-019-14277-w

  日期：——

  however, have been limited in part by their irreversible target engagement. In this study, we report the synthesis of fluorogenic taccalonolide probes that maintain the native biological properties of the potent taccalonolide, AJ. These carefully optimized, cell-permeable probes outperform commercial taxane-based probes and enable direct visualization of taccalonolides in both live and fixed cells with

  他卡洛内酯微管稳定剂共价结合 β-微管蛋白并克服临床相关的紫杉烷耐药机制。然而，对他卡酮内酯的靶标特异性和详细的药物-靶标相互作用的评估在一定程度上受到其不可逆的靶标参与的限制。在这项研究中，我们报告了荧光 taccalonelide 探针的合成，该探针保持了有效的 taccalonelide (AJ) 的天然生物学特性。这些经过精心优化的细胞渗透性探针优于商业紫杉烷探针，并且能够直接可视化活细胞和固定细胞中的塔卡酮内酯，并具有显着的微管共定位。免疫印迹证明了他卡洛内酯与 β-微管蛋白结合的特异性，免疫印迹可以通过利用定点诱变和计算模型进行基于活性的蛋白质分析来确定关键微管蛋白残基和他卡洛内酯部分对药物-靶标相互作用的相对贡献。这种组合方法为研究细胞环境中共价结合药物的结合特异性和分子相互作用提供了一种普遍适用的策略。
• Identification of C-6 as a New Site for Linker Conjugation to the Taccalonolide Microtubule Stabilizers
  作者：Lin Du、April L. Risinger、Samantha S. Yee、Antonius R. B. Ola、Cynthia L. Zammiello、Robert H. Cichewicz、Susan L. Mooberry

  DOI：10.1021/acs.jnatprod.8b01036

  日期：2019.3.22

  bound directly to tubulin and stabilized microtubules. This pharmacological probe has allowed, for the first time, a direct visualization of a taccalonolide binding to microtubules, verifying their cellular binding site. This C-6-modified taccalonolide showed potency comparable to the untagged compound in biochemical experiments; however, its potency was lower in cellular assays, presumably due to decreased

  由于其C-22-C-23环氧化物部分与微管蛋白的共价结合所赋予的独特的微管稳定机制，因此他卡洛奈德是一类微管稳定剂，其绕开了临床上相关的耐药性形式。生成了带有荧光素基团且在C-6上连接有连接基的荧光素的他克洛奈德（8），生化和基于细胞的分析表明，它直接与微管蛋白和稳定的微管结合。该药理探针首次实现了他克洛奈德与微管结合的直接可视化，从而验证了它们的细胞结合位点。在生化实验中，这种C-6修饰的他克洛奈酯显示出与未标记化合物相当的效力；然而，它的功效在细胞分析中较低，大概是由于细胞通透性降低所致。
• TACCALONOLIDE MICROTUBULE STABILIZERS
  申请人：THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

  公开号：US20140357608A1

  公开（公告）日：2014-12-04

  The invention provides epoxytaccalonolide microtubule stabilizers and their use as anti-proliferative microtubule stabilizing agents.

  本发明提供了环氧紫杉醇微管稳定剂及其作为抗增殖微管稳定剂的用途。
• Taccalonolide microtubule stabilizers
  申请人：THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

  公开号：US09340572B2

  公开（公告）日：2016-05-17

  The invention provides epoxytaccalonolide microtubule stabilizers and their use as anti-proliferative microtubule stabilizing agents.

  本发明提供了环氧萜内酯微管稳定剂及其作为抗增殖微管稳定剂的应用。