7,2'-di(O-triethylsilyl)-3'-N-debenzoylpaclitaxel | 168479-09-2

• 英文名称: 7,2'-di(O-triethylsilyl)-3'-N-debenzoylpaclitaxel
• 英文别名: [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-15-[(2R,3S)-3-amino-3-phenyl-2-triethylsilyloxypropanoyl]oxy-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-triethylsilyloxy-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate
• CAS: 168479-09-2
• 化学式: C₅₂H₇₅NO₁₃Si₂
• 分子量: 978.337
• InChiKey: YUHBZYPJXNVTPK-FQGSOGPKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.32
• 重原子数：
  68
• 可旋转键数：
  22
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  196
• 氢给体数：
  2
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  7,2'-di(O-triethylsilyl)-3'-N-debenzoylpaclitaxel 在 吡啶 、 4-二甲氨基吡啶 、 N-乙基二丙胺 、 氢氟酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 13.5h， 生成 [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-15-[(2R,3S)-3-(butylsulfanylcarbonylamino)-2-hydroxy-3-phenylpropanoyl]oxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate
  参考文献：
  名称：

  Structure–activity relationships study at the 3′-N position of paclitaxel. part 2: synthesis and biological evaluation of 3′-N-thiourea- and 3′-N-thiocarbamate-bearing paclitaxel analogues

  摘要：

  The syntheses and preliminary biological evaluation of 3'-N-thiocarbamate- and 3'-N'-thiourea-bearing paclitaxel analogues, 4a-f and 5a-e, are described. 3'-N-thiocarbamates 4a-e were found to be more potent than paclitaxel in both the tubulin polymerization assay and the in vitro cytotoxicity assay. Several derivatives of this class such as 4c, 4d, and 4e also exhibited some in vivo activity. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(00)00242-0
• 作为产物：
  描述：

  [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-15-[(2R,3S)-3-phenyl-3-(phenylmethoxycarbonylamino)-2-triethylsilyloxypropanoyl]oxy-9-triethylsilyloxy-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate 在 palladium dihydroxide 氢气 作用下， 以 乙酸乙酯 为溶剂， 以94%的产率得到7,2'-di(O-triethylsilyl)-3'-N-debenzoylpaclitaxel
  参考文献：
  名称：

  Structure–activity relationships study at the 3′-N position of paclitaxel. part 2: synthesis and biological evaluation of 3′-N-thiourea- and 3′-N-thiocarbamate-bearing paclitaxel analogues

  摘要：

  The syntheses and preliminary biological evaluation of 3'-N-thiocarbamate- and 3'-N'-thiourea-bearing paclitaxel analogues, 4a-f and 5a-e, are described. 3'-N-thiocarbamates 4a-e were found to be more potent than paclitaxel in both the tubulin polymerization assay and the in vitro cytotoxicity assay. Several derivatives of this class such as 4c, 4d, and 4e also exhibited some in vivo activity. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(00)00242-0

文献信息

• A structure-based design of new C2- and C13-substituted taxanes: tubulin binding affinities and extended quantitative structure–activity relationships using comparative binding energy (COMBINE) analysis
  作者：Claire Coderch、Yong Tang、Javier Klett、Shu-En Zhang、Yun-Tao Ma、Wang Shaorong、Ruth Matesanz、Benet Pera、Angeles Canales、Jesús Jiménez-Barbero、Antonio Morreale、J. Fernando Díaz、Wei-Shuo Fang、Federico Gago

  DOI：10.1039/c3ob40407b

  日期：——

  Ten novel taxanes bearing modifications at the C2 and C13 positions of the baccatin core have been synthesized and their binding affinities for mammalian tubulin have been experimentally measured. The design strategy was guided by (i) calculation of interaction energy maps with carbon, nitrogen and oxygen probes within the taxane-binding site of β-tubulin, and (ii) the prospective use of a structure-based QSAR (COMBINE) model derived from an earlier series comprising 47 congeneric taxanes. The tubulin-binding affinity displayed by one of the new compounds (CTX63) proved to be higher than that of docetaxel, and an updated COMBINE model provided a good correlation between the experimental binding free energies and a set of weighted residue-based ligand–receptor interaction energies for 54 out of the 57 compounds studied. The remaining three outliers from the original training series have in common a large unfavourable entropic contribution to the binding free energy that we attribute to taxane preorganization in aqueous solution in a conformation different from that compatible with tubulin binding. Support for this proposal was obtained from solution NMR experiments and molecular dynamics simulations in explicit water. Our results shed additional light on the determinants of tubulin-binding affinity for this important class of antitumour agents and pave the way for further rational structural modifications.

  我们合成了在巴卡丁核心的 C2 和 C13 位置进行修饰的十种新型紫杉醇，并通过实验测定了它们与哺乳动物微管蛋白的结合亲和力。设计策略的指导原则是：(i) 计算δ-微管蛋白的类固醇结合位点内碳、氮和氧探针的相互作用能量图；(ii) 前瞻性地使用基于结构的 QSAR（COMBINE）模型，该模型来自早期由 47 种同源类固醇组成的系列。事实证明，其中一种新化合物（CTX63）与微管蛋白的结合亲和力高于多西他赛，更新后的 COMBINE 模型为所研究的 57 种化合物中的 54 种提供了实验结合自由能与一组基于加权残基的配体与受体相互作用能之间的良好相关性。原始训练系列中的其余三个异常值的共同点是对结合自由能有很大的不利熵贡献，我们将其归因于紫杉烷在水溶液中的预组织构象不同于与管蛋白结合的构象。在显式水溶液中进行的溶液核磁共振实验和分子动力学模拟为这一提议提供了支持。我们的研究结果进一步揭示了这一类重要抗肿瘤药物与小管蛋白结合亲和力的决定因素，并为进一步合理调整结构铺平了道路。