(5R-顺式)-5,6,11,11alpha-四氢-5-(4-羟基-3,5-二甲氧基苯基)-1H,3H-恶唑并(3',4':1,6)吡啶并(3,4-b)吲哚-3-酮 | 129564-92-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: (5R-顺式)-5,6,11,11alpha-四氢-5-(4-羟基-3,5-二甲氧基苯基)-1H,3H-恶唑并(3',4':1,6)吡啶并(3,4-b)吲哚-3-酮
• 英文名称: azatoxin
• 英文别名: (10R,15S)-10-(4-hydroxy-3,5-dimethoxyphenyl)-13-oxa-8,11-diazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(9),2,4,6-tetraen-12-one
• CAS: 129564-92-7
• 化学式: C₂₁H₂₀N₂O₅
• 分子量: 380.4
• InChiKey: MIXLRUYCYZPSOQ-HXPMCKFVSA-N

物化性质

• 沸点：
  674.0±55.0 °C(Predicted)
• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  84
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (5R-顺式)-5,6,11,11alpha-四氢-5-(4-羟基-3,5-二甲氧基苯基)-1H,3H-恶唑并(3',4':1,6)吡啶并(3,4-b)吲哚-3-酮 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 4.0h， 生成 3-((2,6-dimethoxy-4-((5R,11aS)-3-oxo-1,3,5,6,11,11a-hexahydrooxazolo[3',4':1,6]pyrido[3,4-b]indol-5-yl)phenoxy)carbonyl)aminopropanoic acid
  参考文献：
  名称：

  通过与细胞靶向肽结合来“关闭/打开”药物细胞毒性的调节

  摘要：

  使用简单方便的正交保护固相有机合成（SPOS）合成了负载有多种药物的双核氨基酸平台，这些平台可与肽载体偶联。该平台的每个臂均带有通过相同或不同功能基团连接的不同抗癌剂，从而为每种药物提供了离散的化学释放和生物释放特性，并且还可以通过与药物的缀合来“关闭/开启”调节药物的细胞毒性。平台和细胞靶向肽。这种方法的多功能性使得能够高效生产载药平台，并确定有利的药物组合/连接方式，以便随后缀合至靶向癌细胞治疗的载体部分。

  DOI：

  10.1016/j.ejmech.2014.07.073
• 作为产物：
  描述：

  L-色氨醇 在 sodium ethanolate 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 10.0h， 生成 (5R-顺式)-5,6,11,11alpha-四氢-5-(4-羟基-3,5-二甲氧基苯基)-1H,3H-恶唑并(3',4':1,6)吡啶并(3,4-b)吲哚-3-酮
  参考文献：
  名称：

  Inhibition of DNA Topoisomerase II by Azaelliptitoxins Functionalized in the Variable Substituent Domain

  摘要：

  A series of novel C-11-substituted derivatives of azaelliptitoxin (azatoxin) have been synthesized and tested for their inhibitory activity against human DNA topoisomerase II. Incorporation of a C-11 polyamine pr amine resulted in an increase in the intercalation properties of the drug and a decrease of topoisomerase II activity. The structure-activity relationship (SAR) profile of the nonintercalating C-11 anilino azatoxin class follows the SAR of the (anilino)acridine family. 11-(4-Cyanoanilino)azatoxin (14) was found to be the most active analog in this series, exhibiting similar to 10-fold higher activity than azatoxin 12 and etoposide.

  DOI：

  10.1021/jm9508806

文献信息

• [EN] PEPTIDE-BASED MULTIPLE-DRUG DELIVERY VEHICLE<br/>[FR] VÉHICULE D'ADMINISTRATION DE MÉDICAMENTS MULTIPLES À BASE DE PEPTIDES
  申请人：ARIEL-UNIVERSITY RES AND DEV COMPANY LTD

  公开号：WO2017068577A1

  公开（公告）日：2017-04-27

  A molecular structure comprising a targeting moiety, a multi-functional peptide platform and a plurality of controllably released bioactive agents attached thereto is provided herein.

  本文提供了一种包括靶向基团、多功能肽平台和附着在其上的多种可控释放的生物活性剂的分子结构。
• Ratiometric Fluorescence Monitoring of Antibody-Guided Drug Delivery to Cancer Cells
  作者：Dvir Poplinger、Maksym Bokan、Arkadi Hesin、Ebaston Thankarajan、Helena Tuchinsky、Gary Gellerman、Leonid Patsenker

  DOI：10.1021/acs.bioconjchem.1c00205

  日期：2021.8.18

  pharmaceutical assays, including drug delivery monitoring. Nevertheless, these dual-dye conjugates have never been utilized for ratiometric monitoring of antibody (Ab)-guided targeted drug delivery (TDD). Here, we report for the first time on the new, dual-dye TDD system, Cy5s-Ab-Flu-Aza, comprising the switchable fluorescein-based dye (Flu) linked to the anticancer drug azatoxin (Aza), reference pentamethine

  利用来自双染料分子系统的两个独立荧光信号的比率测量有助于提高许多分析、生物分析和药物分析的检测灵敏度和定量，包括药物输送监测。然而，这些双染料偶联物从未用于对抗体 (Ab) 引导的靶向药物递送 (TDD) 进行比例监测。在这里，我们首次报告了新的双染料 TDD 系统 Cy5s-Ab-Flu-Aza，该系统包含与抗癌药物氮杂毒素 (Aza) 连接的可切换荧光素染料 (Flu)，参考五甲川花青染料(Cy5s) 和 Her2 特异性人源化单克隆曲妥珠单抗 (Herceptin) 抗体。该模型系统在体外证明了药物释放的比率荧光监测能力在过表达 Her2 受体的人乳腺癌 SKBR3 细胞系的例子中。用于设计比例、抗体引导 TDD 系统的建议方法，其中“药物可切换染料”偶联物和参考染料独立连接到抗体，可以扩展到其他药物、染料和抗体。用更长波长（红色或近红外）可切换荧光团替代在体内无法检测到的发绿光染料
• Peptide-based multiple-drug delivery vehicle
  申请人：Ariel-University Research and Development Company Ltd.

  公开号：US10478507B2

  公开（公告）日：2019-11-19

  A molecular structure comprising a targeting moiety, a multi-functional peptide platform and a plurality of controllably released bioactive agents attached thereto is provided herein.

  本文提供了一种分子结构，包括一个靶向分子、一个多功能肽平台和附着在其上的多种可控释放的生物活性剂。
• New somatostatin-drug conjugates for effective targeting pancreatic cancer
  作者：E. Ragozin、A. Hesin、A. Bazylevich、H. Tuchinsky、A. Bovina、T. Shekhter Zahavi、M. Oron-Herman、G. Kostenich、M.A. Firer、T. Rubinek、I. Wolf、G. Luboshits、M.Y. Sherman、G. Gellerman

  DOI：10.1016/j.bmc.2018.06.032

  日期：2018.7

  Pancreatic cancer poorly responds to available drugs, and finding novel approaches to target this cancer type is of high significance. Here, based on a common property of pancreatic cancer cells to express somatostatin receptors (SSTR), we designed drug conjugates with novel somatostatin-derived cyclic peptides (SSTp) with broad selectivity towards SSTR types to facilitate drug targeting of the pancreatic cancer cells specifically. Uptake of our newly designed SSTps was facilitated by SSTRs expressed in the pancreatic cancers, including SSTR2, SSTR3, SSTR4 and SSTR5. Three major drugs were conjugated to our best SSTps that served as delivery vehicles, including Camptothecin (CPT), Combretastatin-4A (COMB) and Azatoxin (AZA). All designed drug conjugates demonstrated penetration to pancreatic cancer cell lines, and significant toxicity towards them. Furthermore, the drug conjugates specifically accumulated in tumors in the animal xenograft model, though some accumulation was also seen in kidney. Overall these findings lay the basis for development of novel drug series that could target the fatal pancreatic cancer.
• Structure-activity relationship for DNA topoisomerase II-induced DNA cleavage by azatoxin analogues
  作者：Jose S. Madalengoitia、Jetze J. Tepe、Karl A. Werbovetz、Erich K. Lehnert、Timothy L. Macdonald

  DOI：10.1016/s0968-0896(97)00113-2

  日期：1997.9

  Eighteen analogues of the nonintercalative DNA topoisomerase II (topo II)-active epipodophyllotoxin-ellipticine hybrid, azatoxin, were synthesized and evaluated for their ability to induce topo II-mediated DNA strand breaks in vitro. In general, the SAR profile of the azatoxins showed more homology with that of the epipodophyllotoxins than with the ellipticines. Of the compounds studied, only fluoro substitution at the 8-, 9, and 10-positions of azatoxins enhanced activity, with 9-fluoroazatoxin being the most active compound in this series. (C) 1997 Elsevier Science Ltd.