7,10,13-tri(triethylsilyl)-2-debenzoyl-2-(3-chlorobenzoyl)-10-deacetylbaccatin III | 259522-64-0

• 英文名称: 7,10,13-tri(triethylsilyl)-2-debenzoyl-2-(3-chlorobenzoyl)-10-deacetylbaccatin III
• CAS: 259522-64-0
• 化学式: C₄₇H₇₇ClO₁₀Si₃
• 分子量: 921.832
• InChiKey: DCMLCALOKOFIFW-GLKQYSEKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.82
• 重原子数：
  61.0
• 可旋转键数：
  18.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  126.82
• 氢给体数：
  1.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  7,10,13-tri(triethylsilyl)-2-debenzoyl-2-(3-chlorobenzoyl)-10-deacetylbaccatin III 在 吡啶 、 氟化氢吡啶 作用下， 以 乙腈 为溶剂， 反应 40.0h， 生成 (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-4,6,9,11-tetrahydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-12-yl 3-chlorobenzoate
  参考文献：
  名称：

  新型第二代紫杉烷类化合物的合成及其构效关系。

  摘要：

  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”。

  DOI：

  10.1016/s0960-894x(99)00629-0
• 作为产物：
  描述：

  10-脱乙酰基巴卡丁 III 在 咪唑 、 4-二甲氨基吡啶 、 红铝 、 N,N'-二异丙基碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 7,10,13-tri(triethylsilyl)-2-debenzoyl-2-(3-chlorobenzoyl)-10-deacetylbaccatin III
  参考文献：
  名称：

  新型 3'-二氟乙烯基紫杉类化合物的合成与生物学评价

  摘要：

  一系列具有 C10 修饰以及具有 C2 和 C10 修饰的 3'-二氟乙烯基紫杉醇被战略性地设计为阻断细胞色素 P-450 3A4 酶的代谢并合成。评估了这些新型二氟乙烯基紫杉素对药物敏感的人乳腺 (MCF7)、多药耐药 (MDR) 人卵巢 (NCI/ADR)、人结肠 (HT-29) 和人胰腺 (PANC-1) 癌细胞的细胞毒性线。与紫杉醇相比，3'-二氟乙烯基紫杉醇对 MCF7、HT-29 和 PANC-1 细胞系的活性高出数倍至 16 倍，对 NCI/ADR 细胞系的效力高出三个数量级。构效关系研究表明 C2 修饰对 MDR 癌细胞系的活性至关重要，而 C10 修饰对效力的影响相当小，但有一些例外。C2 修饰对 MCF7 细胞系效力的影响按以下顺序增加：H < F < Cl < N3 . 在评估的 25 种 3'-二氟乙烯基紫杉类中，8 种紫杉类对 MCF7 细胞系的pM IC 50值小于

  DOI：

  10.1016/j.jfluchem.2012.07.007

文献信息

• 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 of potent taxoids for tumor-specific delivery using monoclonal antibodies
  作者：Michael L Miller、Elizabeth E Roller、Xinyaun Wu、Barbara A Leece、Victor S Goldmacher、Ravi V.J Chari、Iwao Ojima

  DOI：10.1016/j.bmcl.2004.05.027

  日期：2004.8

  The targeted delivery of taxoids, in the form of taxane-antibody immunoconjugates, requires the preparation of taxoids containing moieties suitable for their conjugation to monoclonal antibodies. A series of taxoids incorporating a disulfide-containing linker at various positions of the taxoid framework have been prepared to investigate the most suitable position for conjugation. A second series of taxoids modified at the C-2 position aimed at increasing the potency of these taxanes has also been prepared. (C) 2004 Elsevier Ltd. All rights reserved.
• Syntheses and structure–activity relationships of novel 3′-difluoromethyl and 3′-trifluoromethyl-taxoids
  作者：Larissa V. Kuznetsova、Antonella Pepe、Ioana M. Ungureanu、Paula Pera、Ralph J. Bernacki、Iwao Ojima

  DOI：10.1016/j.jfluchem.2008.05.013

  日期：2008.9

  A series of novel 3'-difluoromethyl-taxoids and 3'-trifluoromethyl-taxoids with modifications at the C2 and C10 positions were synthesized and evaluated for their in vitro cytotoxicities against human breast carcinoma (MCF7-S, MCF7-R, LCC6-WT, LCC6-MDR), non-small cell lung carcinoma (H460) and colon adenocarcinoma (HT-29) cell lines. These second-generation fluoro-taxoids exhibited several times to more than 20 times better potency than paclitaxel against drug-sensitive cancer cell lines, MCF7-S, LCC6-WT. H460, and HT-29. These fluoro-taxoids also possess two orders of magnitude higher potency than paclitaxel against drug-resistant cancer cell lines, MCF7-R and LCC6-MDR. Structure-activity relationship study shows the importance of the C10 modification for increasing the activity against multidrug-resistant cancer cell lines. Effects of the C2-benzoate modifications on the potency in the 3'-difluoromethyl-taxoid series are very clear- (i.e., F < MeO < Cl < N-3), while those in the 3'-trifluoromethyl-taxoid series are less obvious. Also, different trends in the sensitivity to the C2-substitution are observed between drug-sensitive cell lines and drug-resistant cancer cell lines that overexpress efflux pumps. (c) 2008 Elsevier B.V. All rights reserved.