2-debenzoyl-2-cyclohexanecarbonyl-7-triethylsilylbaccatin III | 152448-63-0

• 英文名称: 2-debenzoyl-2-cyclohexanecarbonyl-7-triethylsilylbaccatin III
• 英文别名: 2-(cyclohexylcarbonyl)-2-debenzoylbaccatrin III；2-hexahydro-7-(triethylsilyl)baccatin III
• CAS: 152448-63-0
• 化学式: C₃₇H₅₈O₁₁Si
• 分子量: 706.946
• InChiKey: XLWVGCKVZRLTKM-UZBMNOCMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.95
• 重原子数：
  49.0
• 可旋转键数：
  9.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  154.89
• 氢给体数：
  2.0
• 氢受体数：
  11.0

反应信息

• 作为反应物：
  描述：

  2-debenzoyl-2-cyclohexanecarbonyl-7-triethylsilylbaccatin III 在 盐酸 、 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 48.75h， 生成 2-debenzoyl-2-cyclohexanoylpaclitaxel
  参考文献：
  名称：

  Synthesis and Structure-Activity Relationships of New Antitumor Taxoids. Effects of Cyclohexyl Substitution at the C-3' and/or C-2 of Taxotere (Docetaxel)

  摘要：

  Synthesis and cytotoxicity of the new analogs (11-13) of docetaxel possessing cyclohexyl groups instead of phenyl groups at the C-3' and/or C-2 benzoate positions are described. The C-2 cyclohexanecarboxylate analog of paclitaxel(15) is also synthesized for comparison. The potency of these new taxoids were examined for their inhibitory activity for microtubule disassembly and also for their cytotoxicity against murine P388 leukemia cell line as well. as doxorubicin-resistant P388 leukemia cell line (P388/Dox). It is found that 3'-dephenyl-3'-cyclohexyldocetaxel (11) (0.72T) and 2-(hexahydro)docetaxel (12) (0.85T) possess strong inhibitory activity for microtubule disassembly equivalent to docetaxel (0.7T), which is more potent than paclitaxel (1.0T). The results clearly indicate that phenyl or an aromatic group at C-3' or C-2 is not a requisite for strong binding to the microtubules. This finding has opened an avenue for development of new nonaromatic analogs of docetaxel and paclitaxel. 3'-Dephenyl-3'-cyclohexyl-2-(hexahydro)docetaxel (13) (2T) turns out to be a substantially weaker inhibitor. The cytotoxicities of 11-13 against P388 are, however, in the same range that is 8-12 times weaker than docetaxel and 4-6 times weaker than paclitaxel, i.e., 13 shows equivalent cytotoxicity to that of 11 or 12 in spite of much lower microtubule disassembly inhibitory activity. The cytotoxicities of these new taxoids against the P388/Dox cell line are only 2-2.5 times lower than that of docetaxel. The potency of 2-(hexahydro)paclitaxel (15) for these assays is much lower than the docetaxel counterpart 12. The significant loss of activity in vivo against B16 melanoma is observed for 11-13, i.e., 11 is only marginal (T/C = 38% at 20 mg/kg/day), and 12 and 13 are inactive (T/C = 76% and 79%, respectively). This could be ascribed to faster metabolism, faster excretion or other bioavailability problems.

  DOI：

  10.1021/jm00042a013
• 作为产物：
  描述：

  巴卡丁 III 在 吡啶 、 咪唑 、 4-二甲氨基吡啶 、 氢氟酸 、 N,N'-二环己基碳二亚胺 、 红铝 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 0.5h， 生成 2-debenzoyl-2-cyclohexanecarbonyl-7-triethylsilylbaccatin III
  参考文献：
  名称：

  Studies on the photochemistry of taxol®

  摘要：

  Irradiation of taxol at 280 nm in a Rayonet reactor yielded a novel pentacyclic derivative containing a new bond between C-3 and C-II. The proposed mechanism involves a triplet intermediate and the first event of the oxa-di-pi-merhane rearrangement. Taxane derivatives that lack both the benzoate at C-2 and the benzamide function at C-3' do not undergo the rearrangement, suggesting the intervention of an intramolecular energy transfer. Irradiation at 300 nm also effects extrusion of the C-9 carbonyl, yielding a ring-contracted product.

  DOI：

  10.1016/s0040-4020(01)85337-0

文献信息

• The Effect of the Aromatic Rings of Taxol on Biological Activity and Solution Conformation: Synthesis and Evaluation of Saturated Taxol and Taxotere Analogs
  作者：Thomas C. Boge、Richard H. Himes、David G. Vander Velde、Gunda I. Georg

  DOI：10.1021/jm00046a018

  日期：1994.9

  (triethylsilyl)baccatin III. The taxol analogue 15, in which all three taxol phenyl groups are substituted by a cyclohexyl moiety, was synthesized in one step from taxol via hydrogenation. All three analogues (9, 14, and 15) exhibited strong activity in the microtubule assembly assay and cytotoxicity comparable to taxol against B16 melanoma cells. It was also shown that 9, like taxol and taxotere, has an extended

  详细的紫杉醇和紫杉醇的新型环己基类似物的合成和生物学评价。由浆果赤霉素III通过氢化制备2-（环己基羰基）-2-脱苯甲酰基浆果赤霉素III（6）。随后将6与Nt-BOC-3-[（叔丁基二甲基甲硅烷基）氧基] -4-苯基-2-氮杂环丁酮（7）偶联，然后除去保护基，得到2-（环己基羰基）-2-脱苯甲酰基紫杉醇（ 9）。以类似的合成顺序，由N-苯甲酰基-3-[（叔丁基二甲基甲硅烷基）氧基] -4-环己基-2-氮杂环丁酮（12）和（三乙基甲硅烷基）制得3'-环己基-3'-去苯紫杉醇（14）。浆果赤霉素III。由紫杉醇经氢化一步合成了紫杉醇类似物15，其中所有三个紫杉醇苯基均被环己基部分取代。所有三个类似物（9、14，15）在微管组装试验中表现出很强的活性，并具有与紫杉醇相当的针对B16黑色素瘤细胞的细胞毒性。还显示9，像紫杉醇和紫杉醇一样，在氯仿中具有延伸的侧链，但是在DMSO /水混合物中优选采
• 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.
• Structure–activity relationship study of taxoids for their ability to activate murine macrophages as well as inhibit the growth of macrophage-like cells
  作者：Iwao Ojima、Cecilia L Fumero-Oderda、Scott D Kuduk、Zhuping Ma、Fumiko Kirikae、Teruo Kirikae

  DOI：10.1016/s0968-0896(03)00181-0

  日期：2003.7

  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.