(5R,8S,11S)-8-isopropyl-5-methyl-11-((E)-4-(tritylthio)but-1-en-1-yl)-10-oxa-3,17-dithia-7,14,19,20-tetraazatricyclo[14.2.1.12,5]icosa-1(18),2(20),16(19)-triene-6,9,13-trione | 1043577-37-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (5R,8S,11S)-8-isopropyl-5-methyl-11-((E)-4-(tritylthio)but-1-en-1-yl)-10-oxa-3,17-dithia-7,14,19,20-tetraazatricyclo[14.2.1.12,5]icosa-1(18),2(20),16(19)-triene-6,9,13-trione
• 英文别名: (S)-trityl macrocycle；(5R,8S,11S)-5-methyl-8-propan-2-yl-11-[(E)-4-tritylsulfanylbut-1-enyl]-10-oxa-3,17-dithia-7,14,19,20-tetrazatricyclo[14.2.1.12,5]icosa-1(18),2(20),16(19)-triene-6,9,13-trione
• CAS: 1043577-37-2
• 化学式: C₄₀H₄₂N₄O₄S₃
• 分子量: 738.996
• InChiKey: YDENQDZOSHCMIL-FQXXUAGDSA-N

物化性质

• 熔点：
  97-99 °C
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  51
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  189
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (5R,8S,11S)-8-isopropyl-5-methyl-11-((E)-4-(tritylthio)but-1-en-1-yl)-10-oxa-3,17-dithia-7,14,19,20-tetraazatricyclo[14.2.1.12,5]icosa-1(18),2(20),16(19)-triene-6,9,13-trione 在 三异丙基硅烷 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 以95%的产率得到Largazole thiol
  参考文献：
  名称：

  拉格唑的全合成和生物作用模式：一种有效的 I 类组蛋白脱乙酰酶抑制剂

  摘要：

  描述了最近描述的天然物质拉格唑 (1) 及其活性代谢物拉格唑硫醇 (2) 的有效全合成。合成需要八个线性步骤，总产率为 37%。研究表明，拉格唑是一种前药，通过去除 3-羟基-7-巯基庚-4-烯酸部分的辛酰基残基而被激活，生成活性代谢物 2，这是一种非常有效的 I 类组蛋白脱乙酰酶抑制剂。合成的拉格唑和 2 已与 FK228 和 SAHA 一起评估对 HDAC 1、2、3 和 6 的抑制作用。进一步测定了拉格唑和拉格唑硫醇对一组化疗耐药黑色素瘤细胞系的细胞毒性活性，结果表明：发现拉格唑的细胞毒性显着高于拉格唑硫醇；这种差异归因于两种物质的细胞渗透性的差异。

  DOI：

  10.1021/ja8033763
• 作为产物：
  描述：

  三苯甲硫醇 在 咪唑 、 4-二甲氨基吡啶 、 四氯化钛 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 二乙胺 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 20.0h， 生成 (5R,8S,11S)-8-isopropyl-5-methyl-11-((E)-4-(tritylthio)but-1-en-1-yl)-10-oxa-3,17-dithia-7,14,19,20-tetraazatricyclo[14.2.1.12,5]icosa-1(18),2(20),16(19)-triene-6,9,13-trione
  参考文献：
  名称：

  [EN] METHOD FOR PREPARING LARGAZOLE ANALOGS AND USES THEREOF
  [FR] PROCÉDÉ DE PRÉPARATION DE PARTICULES CREUSES ET LEURS UTILISATIONS

  摘要：

  本文描述了类似largazole的类似物。此外，还描述了使用largazole和largazole类似物治疗癌症和血液疾病的方法，以及包含它们的药物组合物。同样描述了制备largazole类似物的方法。

  公开号：

  WO2016144665A1

文献信息

• Method for preparing largazole analogs and uses thereof
  申请人：Williams Robert M.

  公开号：US20100029731A1

  公开（公告）日：2010-02-04

  Analogs of largazole are described herein. Methods of treating cancer and blood disorders using largazole and largazole analogs and pharmaceutical compositions comprising the same are additionally described herein. Methods for preparing largazole analogs are likewise described.

  本文描述了类似largazole的类似物。此外，还描述了使用largazole和largazole类似物治疗癌症和血液疾病的方法，以及包含它们的药物组合物。同样描述了制备largazole类似物的方法。
• Design, synthesis, and biological evaluation of largazole derivatives: alteration of the zinc-binding domain
  作者：Jinyue Su、Yatao Qiu、Kun Ma、Yiwu Yao、Zhen Wang、Xianling Li、Dayong Zhang、Zhengchao Tu、Sheng Jiang

  DOI：10.1016/j.tet.2014.05.078

  日期：2014.10

  A new series of largazole analogues in which the side chain was replaced with disulfide groups were synthesized, and their biological activities were evaluated. Compound 8 bearing an octyl moiety showed much better selectivity for HDAC1 over HDAC7 than largazole (320-fold). Structure activity relationships suggested that the length in the disulfide chain of largazole is important for the selectivity toward HDAC1 over HDAC7. (C) 2014 Elsevier Ltd. All rights reserved.
• Largazole and Analogues with Modified Metal-Binding Motifs Targeting Histone Deacetylases: Synthesis and Biological Evaluation
  作者：Pravin Bhansali、Christin L. Hanigan、Robert A. Casero、L. M. Viranga Tillekeratne

  DOI：10.1021/jm200432a

  日期：2011.11.10

  The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn2+ were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of alpha-tubulin.
• Concise total synthesis of largazole
  作者：Qiong Xiao、Li-Ping Wang、Xiao-Zhen Jiao、Xiao-Yu Liu、Qian Wu、Ping Xie

  DOI：10.1080/10286020.2010.510114

  日期：2010.11

  The concise total synthesis of largazole was accomplished. The key step included the use of the Nagao thiazolidinethione auxiliary for the diastereoselective acetate aldol reaction and it acts as an acylating agent for the peptide formation.
• Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability
  作者：Hanae Benelkebir、Sabrina Marie、Annette L. Hayden、Jason Lyle、Paul M. Loadman、Simon J. Crabb、Graham Packham、A. Ganesan

  DOI：10.1016/j.bmc.2011.02.024

  日期：2011.6

  The total synthesis of largazole and four analogues is reported. All analogues were nanomolar HDAC inhibitors. The antiproliferative activity is driven by lipophilicity and cell permeability. In murine liver homogenates, largazole is rapidly metabolized (half-life <= 5 min) to the thiol which has a half-life of 51 min. (C) 2011 Elsevier Ltd. All rights reserved.