(3R,4S)-1-tert-butoxycarbonyl-3-triisopropylsiloxy-4-(2-methylpropyl)azetidin-2-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: (3R,4S)-1-tert-butoxycarbonyl-3-triisopropylsiloxy-4-(2-methylpropyl)azetidin-2-one
• 英文别名: tert-butyl (2S,3R)-2-(2-methylpropyl)-4-oxo-3-tri(propan-2-yl)silyloxyazetidine-1-carboxylate
• 化学式: C₂₁H₄₁NO₄Si
• 分子量: 399.646
• InChiKey: NVBPASQWZNAZDI-ZWKOTPCHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.74
• 重原子数：
  27
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3R,4S)-1-tert-butoxycarbonyl-3-triisopropylsiloxy-4-(2-methylpropyl)azetidin-2-one 、 异丁酸乙酯 在 lithium diisopropyl amide 作用下， 生成
  参考文献：
  名称：

  Novel route to hydroxy(keto)ethylene dipeptide isosteres through the reaction of N-tBOC-β-lactams with enolates

  摘要：

  Ring-opening coupling reactions of (3R,4S)-1-(BOC)-B-t-3-silyloxy-4-substituted-azetidin-2-ones with lithium enolates of ketones and esters take place smoothly to give the corresponding hydroxy(keto)ethylene dipeptide isosteres in high yields.

  DOI：

  10.1016/0040-4039(95)00825-w
• 作为产物：
  描述：

  (3R,4S)-1-tert-butoxycarbonyl-3-triisopropylsilyloxy-4-(2-methyl-1-propenyl)-2-azetidinone 在 5% Rh/C 、 氢气 作用下， 以100%的产率得到(3R,4S)-1-tert-butoxycarbonyl-3-triisopropylsiloxy-4-(2-methylpropyl)azetidin-2-one
  参考文献：
  名称：

  Novel C-seco-taxoids possessing high potency against paclitaxel-resistant cancer cell lines overexpressing class III β-tubulin

  摘要：

  Novel C-seco-taxoids were synthesized from 10-deacetylbaccatin III and their potencies evaluated against drug-sensitive and drug-resistant cancer cell lines. The drug-resistant cell lines include ovarian cancer cell lines resistant to cisplatin, topotecan, adriamycin and paclitaxel overexpressing class III beta-tubulin, A2780TC1 and A2780TC3. The last two cell lines were selected through chronic exposure of A2780wt to paclitaxel and Pgp blocker cyclosporine. All novel C-seco-taxoids exhibited remarkable potency against A2780TC1 and A2780TC3 cell lines, and no cross resistance to cisplatin- and topotecan-resistant cell lines, A2780CIS and A2780TOP. Four of those C-seco-taxoids exhibit much higher activities than IDN5390 against paclitaxel-resistant cell lines, A2780ADR, A2780TC1 and A2780TC3. SB-CST-10202 possesses the best all-round high potencies across different drug-resistant cell lines. Molecular modeling studies, including molecular dynamics simulations, on the drug-protein complexes of class I and III beta-tubulins were performed to identify possible cause of the remarkable potency of these C-seco-taxoids against paclitaxel-resistant cell lines overexpressing class III beta-tubulin. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.04.070

文献信息

• Synthesis and structure-activity relationships of new second-generation taxoids
  作者：Iwao Ojima、Tao Wang、Michael L. Miller、Songnian Lin、Christopher P. Borella、Xudong Geng、Paula Pera、Rapph J. Bernacki

  DOI：10.1016/s0960-894x(99)00629-0

  日期：1999.12

  A series of second-generation taxoids bearing a substituent on the C-2-benzoyl group and modifications at C-3'/C-10 positions was synthesized. These taxoids exhibited 2-3 orders of magnitude higher potency than that of paclitaxel against drug-resistant human breast cancer cell lines. It is also noteworthy that three taxoids showed almost no difference in activity against drug-resistant and drug-sensitive

  合成了一系列在C-2-苯甲酰基上带有取代基并在C-3'/ C-10位置进行修饰的第二代紫杉醇。这些紫杉醇对紫杉醇抗药性的人乳腺癌细胞系的效能比紫杉醇高2-3个数量级。还值得注意的是，三种类生物碱对抗药性和药物敏感性细胞系的活性几乎没有差异，它们被归类为“高级第二代类生物碱”。
• Design, Synthesis, and Biological Evaluation of New-Generation Taxoids
  作者：Iwao Ojima、Jin Chen、Liang Sun、Christopher P. Borella、Tao Wang、Michael L. Miller、Songnian Lin、Xudong Geng、Larisa Kuznetsova、Chuanxing Qu、David Gallager、Xianrui Zhao、Ilaria Zanardi、Shujun Xia、Susan B. Horwitz、Jon Mallen-St. Clair、Jennifer L. Guerriero、Dafna Bar-Sagi、Jean M. Veith、Paula Pera、Ralph J. Bernacki

  DOI：10.1021/jm800086e

  日期：2008.6.1

  Novel second-generation taxoids with systematic modifications at the C2, C10, and C3'N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third-generation taxoids". 19 (SB-T-1214), 14g(SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in beta-tubulin as well, wherein the drug resistance is mediated by the beta-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.
• Synthesis and Structure−Activity Relationships of Nonaromatic Taxoids:  Effects of Alkyl and Alkenyl Ester Groups on Cytotoxicity
  作者：Iwao Ojima、Scott D. Kuduk、Paula Pera、Jean M. Veith、Ralph J. Bernacki

  DOI：10.1021/jm9606711

  日期：1997.1.1

  Several new nonaromatic taxoids are synthesized by means of the beta-lactam synthon method. These include taxoids modified with 3-methylbut-2-enoate, 3-methylbutanoate, and cyclohexanecarboxylate groups in place of the benzoate at the C-2 position. In addition, taxoids with 2-methylprop-1-enyl, 2-methylpropyl, (E)-prop-1-enyl, and cyclohexyl groups at the C-3' position are also prepared in combination with the modifications at C-2. The alkyl and alkenyl ester groups at C-2 displayed pronounced effects on the in vitro cytotoxicity. Two of the fully aliphatic taxoids possess similar or stronger activity than paclitaxel and docetaxel. It is clear that the 2-benzoate does not play a unique role, and replacement with the appropriate alkyl and alkenyl groups provides taxoids with equivalent or superior activity.
• New and Efficient Coupling Method for the Synthesis of Peptides Bearing the Norstatine Residue and Their Analogs
  作者：Iwao Ojima、Chung Ming Sun、Young Hoon Park

  DOI：10.1021/jo00085a008

  日期：1994.3

  Novel ring-opening coupling reactions of enantiomerically pure (3R,4S)-1-(tert-butoxycarbonyl)-3-hydroxy beta-lactams 1 with various (S)-amino acid esters 2 including proline methyl ester proceed smoothly at ambient temperature to give the corresponding dipeptides 3 bearing the norstatine residue and its analogs in excellent yields. This new coupling method is applicable to solid-phase peptide syntheses.
• 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.