紫杉醇侧链2 | 155371-59-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 中文名称: 紫杉醇侧链2
• 英文名称: (3R,4S)-1-benzoyl-3-triisopropylsilyloxy-4-phenylazetidin-2-one
• 英文别名: (3R,4S)-1-Benzoyl-3-triisopropylsilyloxy-4-phenyl-2-azetidinone；(3R,4S)-1-Benzoyl-4-phenyl-3-((triisopropylsilyl)oxy)azetidin-2-one；(3R,4S)-1-benzoyl-4-phenyl-3-tri(propan-2-yl)silyloxyazetidin-2-one
• CAS: 155371-59-8
• 化学式: C₂₅H₃₃NO₃Si
• 分子量: 423.627
• InChiKey: RKMPTVJJXUTDCL-XZOQPEGZSA-N

物化性质

• 沸点：
  492.4±55.0 °C(Predicted)
• 密度：
  1.09±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.97
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  紫杉醇侧链2 在 吡啶 、 氢氟酸 、 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 生成 2-debenzoyl-2-(3,3-dimethylpent-4-enoyl)paclitaxel
  参考文献：
  名称：

  Structure–activity relationship study of taxoids for their ability to activate murine macrophages as well as inhibit the growth of macrophage-like cells

  摘要：

  A series of new taxoids modified at the C-3', C-3'N, C-10, C-2 and C-7 positions has been designed, synthesized and evaluated for their potency to induce NO and TNF production by peritoneal murine macrophages (Mphi) from LPS-responsive C3H/HeN and LPS-hyporesponsive C3H/HeJ strains and human blood cells, and for their ability to inhibit the growth of Mphi-like cell lines J774.1 and J7.DEF3. The SAR-study has shown that the nature of the substituents at these positions have critical effect on the induction of TNF and NO production by Mphi. Positions G-3' and C-10 are the most flexible and an intriguing effect of the length of the substituents at the C-10 position is observed for taxoids bearing a straight chain alkanoyl moiety. An aromatic group at the C-3'N and C-2 positions is required for the activity, while only hydroxyl or acetyl substituents seem to be tolerated at the C-7 position. The natural stereochemistry in the C-13 isoserine side chain of the taxoids is an absolute requirement for macrophage activation. It has also been clearly shown that there is no correlation between the ability of the taxoids to induce TNF/NO production in C3H/HeN M and the cytotoxicity against Mphi-like cells. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00181-0
• 作为产物：
  描述：

  3-acetoxy-N-(4-methoxyphenyl)-4-phenylazetidin-2-one 在 咪唑 、 ammonium cerium (IV) nitrate 、 (R,S)-Josiphos 、 四磷十氧化物 、 氢气 、 nickel diacetate 、 碳酸氢钠 、 sodium carbonate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， -5.0~80.0 ℃ 、6.0 MPa 条件下， 反应 27.75h， 生成 紫杉醇侧链2
  参考文献：
  名称：

  质子穿梭使镍催化的DKR催化α-酮基-β-内酰胺的不对称还原

  摘要：

  手性α-羟基-β-内酰胺是许多生物活性化合物和抗生素的关键片段，开发有效的合成方法具有重要价值。α-酮-β-内酰胺的高对映选择性动态动力学拆分（DKR）通过一种新颖的质子穿梭策略。Ni催化不对称氢化可有效地和对映选择性地还原各种α-酮-β-内酰胺，从而提供具有高收率和对映选择性的相应α-羟基-β-内酰胺衍生物（最高收率92％，最高收率94％ ee）。氘标记实验表明，苯基次膦酸通过促进烯醇化过程在α-酮-β-内酰胺的DKR中起关键作用。该方案的合成潜力通过其在紫杉酚和（+）- Epi -Cytoxazone关键中间体的合成中的应用得到证明。

  DOI：

  10.1039/d0cc05599a

文献信息

• Synthesis and biological evaluation of C-3′NH/C-10 and C-2/C-10 modified paclitaxel analogues
  作者：Erkan Baloglu、Jeannine M Hoch、Sabarni K Chatterjee、Rudravajhala Ravindra、Susan Bane、David G.I Kingston

  DOI：10.1016/s0968-0896(02)00608-9

  日期：2003.4

  investigating possible synergistic effects. The biological activities of these analogues were evaluated in both a microtubule assembly assay and human ovarian cancer (A2780) and prostate cancer (PC3) cytotoxicity assay. In some cases the doubly modified analogues were more active than would have been predicted based on the activity of the singly modified analogues, indicating probable synergistic effects

  同时研究了紫杉醇在C-3'NH / C-10和C-2 / C-10位置上的修饰，以研究可能的协同作用。在微管组装试验和人卵巢癌（A2780）和前列腺癌（PC3）细胞毒性试验中评估了这些类似物的生物学活性。在某些情况下，双修饰的类似物比基于单修饰的类似物的活性所预测的活性更高，表明可能具有协同作用。
• Synthesis and biological evaluation of novel taxoids designed for targeted delivery to tumors
  作者：Erkan Baloglu、Michael L. Miller、Elizabeth E. Roller、Emily E. Cavanagh、Barbara A. Leece、Victor S. Goldmacher、Ravi V.J. Chari

  DOI：10.1016/j.bmcl.2004.09.025

  日期：2004.12

  they are capable of targeting tumor markers selectively. We have prepared taxoids with significantly higher cytotoxicity than paclitaxel and docetaxel. These taxoids now meet the high potency required for use in a targeted-delivery approach using monoclonal antibodies. The synthesis and biological evaluation of these taxoids are reported.

  药物-抗体缀合物的使用提供了将抗癌药物靶向递送至癌细胞的方法。单独的单克隆抗体通常不具有很高的治疗功效，但是，它们能够选择性地靶向肿瘤标志物。我们准备了比紫杉醇和多西紫杉醇具有明显更高细胞毒性的紫杉烷类药物。现在，这些类紫杉醇可满足使用单克隆抗体进行靶向递送方法所需的高效力。报告了这些类紫杉醇的合成和生物学评估。
• Stereocontrolled Syntheses of C-Aryl Taxanes By Intramolecular Heck Olefination. Novel Instances of Diastereofacial Guidance By Proximal Coordination
  作者：Wendy B. Young、John J. Masters、Samuel Danishefsky

  DOI：10.1021/ja00124a006

  日期：1995.5

  Stereospecific syntheses of baccatin III constructs bearing an aromatic C-ring (2a and 2b) have been demonstrated. A key step involves the use of an intramolecular Heck olefination reaction to form the C-10-C-11 bond (see transformations 15 --> 16 and 27 --> 28). Novel stereospecific reactions en route to 2a and 2b were also discovered (see 8 --> 10, 8 --> 23, 13 --> 14, and 25 --> 26).
• Synthesis and Biological Evaluation of C-Aromataxane Derivatives as P-Glycoprotein-Mediated Multi Drug Resistance Reversal Agents
  作者：Takayuki Doi、Naoko Yamaguchi、Kosuke Ohsawa、Kazuoki Nakai、Masahito Yoshida、Kazuhiro Satake、Yuji Mitani、Hiroshi Nakagawa、Takashi Takahashi、Toshihisa Ishikawa

  DOI：10.3987/com-14-s(k)47

  日期：——

  Synthesis and evaluation of C-aromataxane derivatives as P-glycoprotein-mediated MDR reversal agents have been demonstrated. Several derivatives possessing N-benzoylphenylisoserine at the C2 or C14 position of the template 2a were readily synthesized and were evaluated their affinity for P-glycoprotein. Most of the synthesized derivatives exhibited much lower cytotoxicity in both KB-3-1 cells and MDR KB-G2-cells than paclitaxel (1), and it should be noted that the compound (14R)-5a exhibited high K-m and V-max/K-m values, and cytotoxicity of paclitaxel (1) in MDR KB-G2 cells was significantly recovered (98% reduction, IC50 30 nM) in the presence of 5a (5.0 mu M). The structural features such as endo-cage conformation and the stereochemistry at the C14 position is crucial to exhibit an excellent affinity for P-glycoprotein.
• Syntheses and Structure−Activity Relationships of Novel Nor-seco Taxoids
  作者：Iwao Ojima、Songnian Lin、Subrata Chakravarty、Ivana Fenoglio、Young Hoon Park、Chung-Ming Sun、Giovanni Appendino、Paula Pera、Jean M. Veith、Ralph J. Bernacki

  DOI：10.1021/jo971953r

  日期：1998.3.1

  A series of novel nor-seco taxoids (4a-b, 5a-d, 6), including either a C-13 ester linkage or a C-13 amide linkage, was synthesized by means of the p-lactam synthon method using the coupling of (3R,4S)-1-acyl-beta-lactams with properly protected nor-seco baccatin III derivatives (1, 2, 3) as the key step. Nor-seco baccatin III derivatives were prepared through oxidative cleavage of the A ring of 14 beta-hydroxy-10-deacetylbaccatin III followed by reduction, amination using Mitsunobu conditions, or reductive amination. Nor-seco taxoids with a C-13 ester linkage (4a-b) or a C-13 N-Me amide linkage (6) show reduced cytotoxicity against human cancer cell lines as compared with paclitaxel, but still retain a certain level of activity despite the destruction of the taxane A ring. However, none of the analogues with a C-13 N-H amide linkage (5a-d) exhibit appreciable activity (IC50 > 1.0 mu M). A restrained molecular dynamics study reveals the inability of 5a-d to attain the proposed bioactive conformation, which accounts for the loss of activity.