allyl N-[(S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-(4-methoxyphenyl)-propanoyl]-N-methyl-L-alanyl-N-methyl-L-isoleucinate | 878626-70-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: allyl N-[(S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-(4-methoxyphenyl)-propanoyl]-N-methyl-L-alanyl-N-methyl-L-isoleucinate
• 英文别名: FmocTyr(O-Me)-MeAla-MeIle-OAllyl；N-Fmoc-Tyr(O-Me)-(N-Me)Ala-(N-Me)Ile-OAllyl；Allyl N-(N-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoyl)-N-methyl-L-alanyl)-N-methyl-L-isoleucinate；prop-2-enyl (2S,3S)-2-[[(2S)-2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-methoxyphenyl)propanoyl]-methylamino]propanoyl]-methylamino]-3-methylpentanoate
• CAS: 878626-70-1
• 化学式: C₃₉H₄₇N₃O₇
• 分子量: 669.818
• InChiKey: XXLNRLZYFLMVLR-FETLZDPOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  49
• 可旋转键数：
  17
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  115
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  allyl N-[(S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-(4-methoxyphenyl)-propanoyl]-N-methyl-L-alanyl-N-methyl-L-isoleucinate 在 四(三苯基膦)钯 、 二乙胺 、 N,N-二异丙基乙胺 、 ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) 、 N-甲基苯胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 17.5h， 生成 apratoxin S4
  参考文献：
  名称：

  [EN] MACROCYCLIC THERAPEUTIC AGENTS, METHODS OF MANUFACTURE, AND METHODS OF TREATMENT
  [FR] AGENTS THÉRAPEUTIQUES MACROCYCLIQUES, DES MÉTHODES DE FABRICATION, ET MÉTHODES DE TRAITEMENT

  摘要：

  本发明描述了具有治疗活性的大环化合物，以及治疗自身免疫疾病、炎症、癌症、肿瘤和与细胞增殖有关的疾病的机制和方法。

  公开号：

  WO2015127161A1
• 作为产物：
  描述：

  (2S,3S)-allyl 2-(tert-butoxycarbonyl(methyl)amino)-3-methylpentanoate 在 盐酸 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， 反应 13.0h， 生成 allyl N-[(S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-(4-methoxyphenyl)-propanoyl]-N-methyl-L-alanyl-N-methyl-L-isoleucinate
  参考文献：
  名称：

  系统化学诱变鉴定了一种有效的新型 Apratoxin A/E 杂交体，具有改善的体内抗肿瘤活性

  摘要：

  Apratoxins 是具有细胞毒性的海洋天然产物，可防止分泌途径早期的共翻译易位。我们发现 apratoxin 会下调受体和生长因子配体，对癌细胞，特别是那些依赖自分泌环的细胞，给予一到两次的打击。通过全合成，我们测试了氨基酸取代（包括丙氨酸扫描）对受体酪氨酸激酶和血管内皮生长因子 A（VEGF-A）下调的影响，并通过选定手性中心的差向异构化探测了靶标参与的立体特异性。对两种分泌分子的不同作用表明，可以通过结构修饰调整阿普雷毒素对分泌抑制的底物选择性，以提供量身定制的治疗。

  DOI：

  10.1021/ml200176m

文献信息

• Asymmetric Synthesis of Apratoxin E
  作者：Zhuo-Ya Mao、Chang-Mei Si、Yi-Wen Liu、Han-Qing Dong、Bang-Guo Wei、Guo-Qiang Lin

  DOI：10.1021/acs.joc.6b02086

  日期：2016.10.21

  An efficient method for asymmetric synthesis of apratoxin E 2 is described in this report. The chiral lactone 8, recycled from the degradation of saponin glycosides, was utilized to prepare the non-peptide fragment 6. In addition to this “from nature to nature” strategy, olefin cross-metathesis (CM) was applied as an alternative approach for the formation of the double bond. Moreover, pentafluorophenyl

  该报告描述了一种高效的不对称合成人毒素E 2的方法。从皂苷苷的降解中回收的手性内酯8用于制备非肽片段6。除了这种“从自然到自然”的策略外，还采用了烯烃交叉复分解（CM）作为形成双键的替代方法。此外，发现五氟苯基二苯基次膦酸酯是用于大环化的有效缩合剂。
• Total Synthesis of (−)-Apratoxin A, 34-Epimer, and Its Oxazoline Analogue
  作者：Yoshitaka Numajiri、Takashi Takahashi、Takayuki Doi

  DOI：10.1002/asia.200800365

  日期：2009.1.5

  convergent total synthesis of the highly cytotoxic marine natural product apratoxin A is accomplished by an 18‐step linear sequence. The high sensitivity of the thiazoline, bearing an adjacent β‐hydroxyl group at the C35‐position, results in the assembly process requiring the inclusion of appropriate protecting groups and the careful optimization of all individual transformations. In the synthesis of 3,7‐dihydroxy‐2

  通过18个步骤的线性序列即可完成高度收敛的高度细胞毒性海洋天然产物Apratoxin A的简明和收敛性合成。噻唑啉具有很高的敏感性，在C35位带有一个相邻的β-羟基，导致组装过程中需要包括适当的保护基并仔细优化所有单独的转化。在3,7-二羟基-2-5,8,8-四甲基壬酸（Dtena）的合成中，三个试剂控制的不对称反应使我们能够在二羟基化脂肪酸部分引入四个手性碳中心。成功地证明了受阻酯的形成和空间不利的N-甲基酰胺键。Tf 2 O和Ph合成了Apratoxin A中的噻唑啉3 PO介导的脱水环化作用，在N-甲基异亮氨酸和脯氨酸残基之间实现了最终的大环化。此外，也已经以类似的方式对恶唑啉类似物和Apratoxin A的C34差向异构体进行了详细的阐述。该合成途径将使得能够组装在Dtena的立体中心及其氨基酸方面不同的其他类似物。
• Total synthesis of apratoxin A and B using Matteson's homologation approach
  作者：Oliver Andler、Uli Kazmaier

  DOI：10.1039/d1ob00713k

  日期：——

  Apratoxin A and B, two members of an interesting class of marine cyclodepsipeptides are synthesized in a straightforward manner via Matteson homologation. Starting from a chiral boronic ester, the polyketide fragment of the apratoxins was obtained via five successive homologation steps in an overall yield of 27% and very good diastereoselectivity. This approach is highly flexible and should allow modification

  Apratoxin A 和 B 是一类有趣的海洋环缩肽的两个成员，通过Matteson 同源化以简单的方式合成。从手性硼酸酯开始，通过五个连续的同源化步骤获得了阿普拉毒素的聚酮化合物片段，总产率为 27%，非对映选择性非常好。这种方法非常灵活，也应该允许对这部分天然产物进行修饰，而以前的修饰主要是在肽片段中进行的。
• Synthesis and biological evaluation of oxoapratoxin E and its C30 epimer
  作者：Ping Wu、Hao Xu、Zhi Li、Yang Zhou、Yingxia Li、Wei Zhang

  DOI：10.1016/j.tetlet.2017.07.046

  日期：2017.8

  30R- and 30S-oxazoline analogues of apratoxin E have been prepared with late-stage formation of an oxazoline ring. These two compounds have a potent inhibitory effect on HCT-116 cell proliferation with IC50 values of 345 and 638 nM, respectively. These results suggest that apratoxin E oxazoline bioisosteres are approximately 6-fold less potent than their thiazoline parent compounds. A positive impact

  制备了毒素R的30 R-和30 S-恶唑啉类似物，并在后期形成了恶唑啉环。这两种化合物对HCT-116细胞的增殖具有有效的抑制作用，IC 50值分别为345和638 nM。这些结果表明，Apratoxin E恶唑啉生物等效率比其噻唑啉母体化合物的效力低约6倍。还观察到30 R构象对抗增殖活性的积极影响，与30 S差向异构体相比，增强了约2倍。
• Improved Total Synthesis and Biological Evaluation of Potent Apratoxin S4 Based Anticancer Agents with Differential Stability and Further Enhanced Activity
  作者：Qi-Yin Chen、Yanxia Liu、Weijing Cai、Hendrik Luesch

  DOI：10.1021/jm4019965

  日期：2014.4.10

  Apratoxins are cytotoxic natural products originally isolated from marine cyanobacteria that act by preventing cotranslational translocation early in the secretory pathway to downregulate receptor levels and inhibit growth factor secretion, leading to potent antiproliferative activity. Through rational design and total synthesis of an apratoxin A/ E hybrid, apratoxin S4 (1a), we have previously improved the antitumor activity and tolerability in vivo. Compound la and newly designed analogues apratoxins S7-S9 (1b-d), with various degrees of methylation at C34 (1b,c) or epimeric configuration at C30 (1d), were efficiently synthesized utilizing improved procedures. Optimizations have been applied to the synthesis of key intermediate aldehyde 7 and further include the application of Leighton's silanes and modifications of Kelly's methods to induce thiazoline ring formation in other crucial steps of the apratoxin synthesis. Apratoxin S9 (1d) exhibited increased activity with subnanomolar potency. Apratoxin S8 (lc) lacks the propensity to be deactivated by dehydration and showed efficacy in a human HCT116 xenograft mouse model.