(-)-N¹³-desmethylindolactam V | 90365-52-9

• 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: (-)-N¹³-desmethylindolactam V
• 英文别名: des-methyl-(-)-indolactam V；(10S,13S)-13-(hydroxymethyl)-10-propan-2-yl-3,9,12-triazatricyclo[6.6.1.04,15]pentadeca-1,4(15),5,7-tetraen-11-one
• CAS: 90365-52-9
• 化学式: C₁₆H₂₁N₃O₂
• 分子量: 287.362
• InChiKey: AXVANMLUKNGODF-NHYWBVRUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  77.2
• 氢给体数：
  4
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (-)-N¹³-desmethylindolactam V 在 palladium on activated charcoal 氢气 、 氢气 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Natural Product Synthesis on Polymeric Supports—Synthesis and Biological Evaluation of an Indolactam Library

  摘要：

  Potent activators of protein kinase C in fibroblasts: This property was determined for several indolactam V analogues (1) with a new cell-based assay system. This tumor-promoting indole alkaloid and analogues thereof can be synthesized efficiently on the solid phase. The key steps of the combinatorial approach are a regioselective amination of the indole ring and an enantioselective enzymatic reaction.

  DOI：

  10.1002/(sici)1521-3773(19991004)38:19<2902::aid-anie2902>3.0.co;2-2
• 作为产物：
  描述：

  D-缬氨酸 在 palladium on activated charcoal N-甲基吗啉 、 2,6-二甲基吡啶 、 sodium tetrahydroborate 、 氯化亚砜 、 Proton Sponge 、 硫酸 、 氢气 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 1-羟基苯并三唑 、 (+)-10-camphorsulfonic acid 、 sodium nitrite 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 苯 为溶剂， -78.0~70.0 ℃ 、344.73 kPa 条件下， 反应 141.5h， 生成 (-)-N¹³-desmethylindolactam V
  参考文献：
  名称：

  （-）-吲哚内酰胺-V的区域和立体控制的全合成

  摘要：

  由L-色氨酸甲酯以10个步骤制备（-）-吲哚内酰胺-V（IL-V）（1），总产率为17.1％。关键步骤包括酰基环中间体（4）的区域特异的thallation ，然后叠氮化物置换和还原以引入13-氨基。通过衍生自D-缬氨酸的手性膨胀剂（10）的S N 2置换来实现对C-11立体中心的控制。al介导的二肽的封闭（17）没有提供替代途径通往IL-V。

  DOI：

  10.1016/s0040-4020(01)87853-4

文献信息

• Synthetic Indolactam V Analogues as Inhibitors of PAR2-Induced Calcium Mobilization in Triple-Negative Breast Cancer Cells
  作者：Jan Stein、Sonja Stahn、Jörg-M. Neudörfl、Julia Sperlich、Hans-Günther Schmalz、Nicole Teusch

  DOI：10.1002/cmdc.201700640

  日期：2018.1.22

  anticancer therapy, as it plays a critical role in cell migration and invasion. Selective PAR2 inhibitors therefore have potential as anti‐metastatic drugs. Knowing that the natural product teleocidin A2 is able to inhibit PAR2 in tumor cells, the goal of the present study was to elaborate structure–activity relationships and to identify potent PAR2 inhibitors with lower activity against the adverse target

  人蛋白酶激活受体2（PAR2）是一种跨膜G蛋白偶联受体（GPCR），是新型抗癌治疗的引人注目的靶标，因为它在细胞迁移和侵袭中起着至关重要的作用。因此，选择性PAR2抑制剂具有作为抗转移药物的潜力。知道天然产物telociocidin A2能够抑制肿瘤细胞中的PAR2，因此本研究的目的是阐明结构与活性之间的关系，并确定对有害靶标蛋白激酶C（PKC）具有较低活性的有效PAR2抑制剂。为了这个目的，开发了吲哚内酰胺V的有效的克级全合成（即，所有teleocidins的母体结构），并制备了衍生物库。实际上，发现某些化合物在低纳摩尔浓度下具有较高的选择性（相对于Teleocidin A2）作为PAR2抑制剂。桥联吲哚核的C3和C4位置的伪肽片段被证明对靶标结合至关重要，而活性和靶标选择性则取决于N1或C7处的取代基。这项研究揭示了新型衍生物，在PAR2拮抗作用中表现出很高的功效，并具有更高的选择性。
• Total synthesis of (−)-indolactam V
  作者：Zhengren Xu、Fengying Zhang、Lihe Zhang、Yanxing Jia

  DOI：10.1039/c0ob01115k

  日期：——

  The total synthesis of protein kinase C activator (−)-indolactam V (IL-V) has been successfully completed with two separate approaches: From known 4-nitrotryptophan derivative 3 in 8 steps (49% overall yield) and from L-glutamic acid in 12 steps (18% overall yield), where 4-nitrotryptophanol derivative 4 served as a key intermediate. Derivatives 3 and 4, both incorporating indole 4-substitution and

  蛋白激酶C激活剂（-）-吲哚内酰胺V（IL-V）的总合成已通过两种单独的方法成功完成：分8步从已知的4-硝基色氨酸衍生物3（总收率49％）和从大号谷氨酸分12步（总收率18％）进行研究，其中4-硝基色氨酸衍生物4为关键中间体。衍生物3和4均在IL-V中结合了吲哚4取代基和C-9立体中心，分别通过Pd催化的吲哚合成，由3-硝基-2-碘苯胺5与醛6和7合成。同时，醛7是由大号谷氨酸分5步（68％收率）。使用HATU在THF中以良好的产率实现9元环的内酰胺化。
• Synthesis and stereochemistry of indolactam-v, an active fragment of teleocidins. Structural requirements for tumor-promoting activity
  作者：Yasuyuki Endo、Koichi Shudo、Akiko Itai、Masashi Hasegawa、Shin-ichiro Sakai

  DOI：10.1016/s0040-4020(01)96073-9

  日期：——
• Synthesis and Biological Activities of New Conformationally Restricted Analogues of (−)-Indolactam-V:  Elucidation of the Biologically Active Conformation of the Tumor-Promoting Teleocidins
  作者：Kazuhiro Irie、Tomomi Isaka、Yoriko Iwata、Yoshiaki Yanai、Yoshimasa Nakamura、Fumito Koizumi、Hajime Ohigashi、Paul A. Wender、Yoshiko Satomi、Hoyoku Nishino

  DOI：10.1021/ja961727j

  日期：1996.1.1

  The tumor-promoting teleocidins and their core structure (-)-indolactam-V (1) exist in two stable conformers in solution at room temperature. The cis amide assumes a twist conformation while the trans amide exists in a sofa form. In order to identify the biologically active conformation of the teleocidins, we have synthesized new twist-restricted analogues 5a and 6 based on an aza-Claisen rearrangement of (-)-N-13-desmethyl-N-13-allylindolactam-V (3) and a sofa-restricted analogue, (-)-5-methylindolactam-V (22). The activities of these new compounds were evaluated in three in vitro bioassays associated with in vivo tumor-promoting activity: binding to the protein kinase C regulatory domain, induction of the Epstein-Barr virus early antigen, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. These three biological activities correlated well for each derivative, Twist-restricted analogues 5a and 6 showed significant activities in the three assays, comparable to 1 itself. In contrast, sofa-restricted 22 showed little activity related to tumor promotion. Introduction of a prenyl group into position 7 or 18 of 5a and 6 significantly enhanced the activity while sofa-restricted (-)-5-prenylindolactam-V (23) showed only very weak activity. These results indicate that the active conformation of the teleocidins and 1 is close to the twist form. This is the first evidence beating on the active conformation of the teleocidins based on conformationally restricted analogues with an intact indolactam skeleton and is in accord with conclusions reported for benzolactams, analogues without the pyrrole moiety. This study also describes the synthesis of hew biologically active compounds (26a, 26b, 28) based on inactive (+)-epiindolactam-V (24), involving a further application of the aza-Claisen rearrangement. Bridge formation between positions 5 and 13 of indolactam derivatives represents a particularly effective analogue design strategy, allowing for the remote control of the conformation of this ring system and for the introduction of a wide range of structural variations, as required for the development of new protein kinase C activators with high isozyme selectivity.
• Irie, Kazuhiro; Hagiwara, Nobuyuki; Funaki, Atsushi, Agricultural and Biological Chemistry, 1988, vol. 52, # 12, p. 3193 - 3196
  作者：Irie, Kazuhiro、Hagiwara, Nobuyuki、Funaki, Atsushi、Hayashi, Hideo、Arai, Motoo、et al.

  DOI：——

  日期：——