10-acetyl-3'-dephenyl-3'-(2-methylprop-1-enyl)-7-triethylsilyl-2'-triisopropylsilyldocetaxel | 485801-36-3

• 英文名称: 10-acetyl-3'-dephenyl-3'-(2-methylprop-1-enyl)-7-triethylsilyl-2'-triisopropylsilyldocetaxel
• 英文别名: 7-triethylsilyl-10-acetyl-2'-triisopropyl-3'-dephenyl-(2-methylprop-1-enyl)docetaxel
• CAS: 485801-36-3
• 化学式: C₅₈H₉₁NO₁₅Si₂
• 分子量: 1098.53
• InChiKey: NWBAPRQKRIUFEH-OXVIPHJYSA-N

物化性质

• 沸点：
  920.2±65.0 °C(Predicted)
• 密度：
  1.15±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  10.65
• 重原子数：
  76.0
• 可旋转键数：
  19.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  208.52
• 氢给体数：
  2.0
• 氢受体数：
  15.0

反应信息

• 作为反应物：
  描述：

  10-acetyl-3'-dephenyl-3'-(2-methylprop-1-enyl)-7-triethylsilyl-2'-triisopropylsilyldocetaxel 在 吡啶 、 氢氟酸 作用下， 以 乙腈 为溶剂， 反应 5.0h， 以90%的产率得到3'-dephenyl-3'-(2-methyl-1-propenyl)-10-acetyldocetaxel
  参考文献：
  名称：

  Syntheses and Structure−Activity Relationships of the Second-Generation Antitumor Taxoids:  Exceptional Activity against Drug-Resistant Cancer Cells

  摘要：

  A series of new 3'-(2-methyl-1-propenyl) and 3'-(2-methylpropyl) taxoids with modifications at C-10 was synthesized by means of the beta-lactam synthon method using 10-modified 7-(triethylsilyl)-10-deacetylbaccatin III derivatives. The new taxoids thus synthesized show excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines. All but one of these new taxoids possess better activity than paclitaxel and docetaxel in the same assay, i.e., the IC50 values of almost all the taxoids are in the subnanomolar level. It is found that a variety of modifications at C-10 is tolerated for the activity against normal cancer cell lines, but the activity against a drug-resistant human breast cancer cell line expressing MDR phenotype (MCF7-R) is highly dependent on the structure of the C-10 modifier. A number of the new taxoids exhibit remarkable activity (IC50 = 2.1-9.1 nM) against MCF7-R. Among these, three new taxoids, SB-T-1213 (4a), SB-T-1214 (4b), and SB-T-1102 (5a), are found to be exceptionally potent, possessing 2 orders of magnitude better activity than paclitaxel and docetaxel. The observed exceptional activity of these taxoids may well be ascribed to an effective inhibition of P-glycoprotein binding by the modified C-10 moieties. The new taxoid SB-T-1213 (4a) shows an excellent activity (T/C = 0% at 12.4 and 7.7 mg/kg/dose, log(10) cell kill = 2.3 and 2.0, respectively) against B16 melanoma in B6D2F(1) mice via intravenous administration.

  DOI：

  10.1021/jm9604080
• 作为产物：
  描述：

  10-脱乙酰基巴卡丁 III 在 咪唑 、 sodium hexamethyldisilazane 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 10-acetyl-3'-dephenyl-3'-(2-methylprop-1-enyl)-7-triethylsilyl-2'-triisopropylsilyldocetaxel
  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

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.
• Tumor-Specific Novel Taxoid−Monoclonal Antibody Conjugates
  作者：Iwao Ojima、Xudong Geng、Xinyuan Wu、Chuanxing Qu、Christopher P. Borella、Hongsheng Xie、Sharon D. Wilhelm、Barbara A. Leece、Laura M. Bartle、Victor S. Goldmacher、Ravi V. J. Chari

  DOI：10.1021/jm025540g

  日期：2002.12.1

  Taxoids: bearing methyldisulfanyl(alkanoyl) groups for taxoid-antibody immunoconjugates were designed, synthesized and their activities evaluated. A highly cytotoxic C-10 methyldisuffanylpropanoyl taxoid was conjugated to monoclonal antibodies recognizing the epidermal growth factor receptor (EGFR) expressed in human squamous cancers. These conjugates were shown to possess remarkable target-specific antitumor activity in vivo against EGFR-expressing A431 tumor xenografts in severe combined immune deficiency mice, resulting in complete inhibition of tumor growth in all the treated mice.