ketotaxol | 1053213-23-2

• 英文名称: ketotaxol
• 英文别名: [(1S,2R)-1-benzamido-3-[[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-2-benzoyloxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-15-yl]oxy]-3-oxo-1-phenylpropan-2-yl] 4-acetylbenzoate
• CAS: 1053213-23-2
• 化学式: C₅₆H₅₇NO₁₆
• 分子量: 1000.07
• InChiKey: DGHFFJZNEUPREW-VYXKMJKBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  73
• 可旋转键数：
  18
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  244
• 氢给体数：
  3
• 氢受体数：
  16

反应信息

• 作为反应物：
  描述：

  4-maleimidobenzoic acid hydrazide trifluoroacetate 、 ketotaxol 在 三氟乙酸 作用下， 以 甲醇 为溶剂， 生成
  参考文献：
  名称：

  Synthesis and In vitro efficacy of acid-Sensitive poly(ethylene glycol) paclitaxel conjugates

  摘要：

  Three maleimide derivatives of the anticancer drug paclitaxel that incorporate an acid-sensitive carboxylic hydrazone linker were prepared and coupled to bifunctional PEGs (MW 20,000 g/mol), The conjugates showed in vitro activity in three human cancer lines in the low micromolar range. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)01002-8
• 作为产物：
  描述：

  4-乙酰基苯甲酸 在 氯化亚砜 、 三乙胺 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 13.0h， 生成 ketotaxol
  参考文献：
  名称：

  Synthesis and In vitro efficacy of acid-Sensitive poly(ethylene glycol) paclitaxel conjugates

  摘要：

  Three maleimide derivatives of the anticancer drug paclitaxel that incorporate an acid-sensitive carboxylic hydrazone linker were prepared and coupled to bifunctional PEGs (MW 20,000 g/mol), The conjugates showed in vitro activity in three human cancer lines in the low micromolar range. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)01002-8

文献信息

• PEGylated dendritic polyglycerol conjugate targeting NCAM-expressing neuroblastoma: Limitations and challenges
  作者：Laura Isabel Vossen、Ela Markovsky、Anat Eldar-Boock、Harald Rune Tschiche、Stefanie Wedepohl、Evgeny Pisarevsky、Ronit Satchi-Fainaro、Marcelo Calderón

  DOI：10.1016/j.nano.2018.02.009

  日期：2018.6

  Neural cell adhesion molecule (NCAM) is found to be a stem-cell marker in several tumor types and its overexpression is known to correlate with increased metastatic capacity. To combine extravasation- and ligand-dependent targeting to NCAM overexpressing-cells in the tumor microenvironment, we developed a PEGylated NCAM-targeted dendritic polyglycerol (PG) conjugate. Here, we describe the synthesis, physico-chemical

  神经细胞粘附分子（NCAM）被发现是几种肿瘤类型中的干细胞标志物，已知其过度表达与转移能力增强相关。为了结合在肿瘤微环境中对NCAM过表达细胞的外渗和配体依赖性靶向，我们开发了PEG化的NCAM靶向树突状聚甘油（PG）共轭物。在这里，我们描述了携带有丝分裂抑制剂紫杉醇（PTX）和NCAM靶向肽（NTP）的PG共轭物的合成，理化性质和生物学评估。评估了PG-NTP-PTX-PEG在体外和体内抑制神经母细胞瘤进展的能力与非靶向衍生物和游离药物相比。NCAM靶向缀合物抑制增殖的内皮细胞的迁移，表明它能够抑制肿瘤血管生成。与非靶向对照相比，靶向缀合物提供了对IMR-32细胞改善的结合和摄取。但是，这些结果并未转化为我们的原位神经母细胞瘤小鼠体内模型。
• Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome
  作者：Shiran Ferber、Galia Tiram、Ana Sousa-Herves、Anat Eldar-Boock、Adva Krivitsky、Anna Scomparin、Eilam Yeini、Paula Ofek、Dikla Ben-Shushan、Laura Isabel Vossen、Kai Licha、Rachel Grossman、Zvi Ram、Jack Henkin、Eytan Ruppin、Noam Auslander、Rainer Haag、Marcelo Calderón、Ronit Satchi-Fainaro

  DOI：10.7554/elife.25281

  日期：——

  Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate (dPGS) nanocarrier. dPGS is able to cross the BBB

  胶质母细胞瘤是一种高度侵袭性的脑肿瘤。当前的护理标准导致边缘化的治疗结果，部分原因是由于获得了耐药性以及化疗药物的血脑屏障（BBB）渗透不足。为了规避这些限制，我们将化疗紫杉醇（PTX）与树突状聚甘油硫酸盐（dPGS）纳米载体偶联。dPGS能够穿过BBB，与P / L-选择素结合并选择性地在颅内肿瘤中蓄积。我们发现dPGS具有双重靶向特性，因为我们发现P-选择素不仅在肿瘤内皮上表达，而且在胶质母细胞瘤细胞上表达。我们提供了dPGS-PTX与抗血管生成蛋白血小板反应蛋白1（TSP-1 PM）的拟肽组合。这种组合通过诱导Fas和Fas-L对颅内人和鼠胶质母细胞瘤产生了显着的协同抗癌作用，与游离PTX或替莫唑胺相比没有副作用。这项研究表明，我们独特的治疗方法为胶质母细胞瘤的治疗提供了可行的替代方法。
• Integrin-targeted nano-sized polymeric systems for paclitaxel conjugation: a comparative study
  作者：Anat Eldar-Boock、Rachel Blau、Claudia Ryppa、Hemda Baabur-Cohen、Ariel Many、María Jesús Vicent、Felix Kratz、Joaquin Sanchis、Ronit Satchi-Fainaro

  DOI：10.1080/1061186x.2017.1358727

  日期：2017.11.26

  The generation of rationally designed polymer therapeutics via the conjugation of low molecular weight anti-cancer drugs to water-soluble polymeric nanocarriers aims to improve the therapeutic index. Here, we focus on applying polymer therapeutics to target two cell compartments simultaneously - tumour cells and angiogenic endothelial cells. Comparing different polymeric backbones carrying the same therapeutic agent and targeting moiety may shed light on any correlation between the choice of polymer and the anti-cancer activity of the conjugate. Here, we compared three paclitaxel (PTX)-bound conjugates with poly-l-glutamic acid (PGA, 4.9mol%), 2-hydroxypropylmethacrylamide (HPMA, 1.2mol%) copolymer, or polyethyleneglycol (PEG, 1:1 conjugate). PGA and HPMA copolymers are multivalent polymers that allow the conjugation of multiple compounds within the same polymer backbone, while PEG is a bivalent commercially available Food and Drug Administration (FDA)-approved polymer. We further conjugated PGA-PTX and PEG-PTX with the integrin alpha(v)beta(3)-targeting moiety RGD (5.5mol% and 1:1 conjugate, respectively). We based our selection on the overexpression of integrin alpha(v)beta(3) on angiogenic endothelial cells and several types of cancer cells. Our findings suggest that the polymer structure has major effect on the conjugate's activity on different tumour compartments. A multivalent PGA-PTX-E-[c(RGDfK)(2)] conjugate displayed a stronger inhibitory effect on the endothelial compartment, showing a 50% inhibition of the migration of human umbilical vein endothelial cell cells, while a PTX-PEG-E-[c(RGDfK)(2)] conjugate possessed enhanced anti-cancer activity on MDA-MB-231 tumour cells (IC50 = 20 nM versus IC50 300 nM for the PGA conjugate).