3'-N-(desmethyl)-3'-N-(4-ethynylbenzyl)clarithromycin | 1093856-94-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3'-N-(desmethyl)-3'-N-(4-ethynylbenzyl)clarithromycin
• 英文别名: 4'-ethynylbenzylclarithromycin；(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-6-[(2S,3R,4S,6R)-4-[(4-ethynylphenyl)methyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-12,13-dihydroxy-4-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-7-methoxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione
• CAS: 1093856-94-0
• 化学式: C₄₆H₇₃NO₁₃
• 分子量: 848.085
• InChiKey: CUYFJMGBNXREKR-YTXIHCGXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  60
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  183
• 氢给体数：
  4
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  3'-N-(desmethyl)-3'-N-(4-ethynylbenzyl)clarithromycin 在 盐酸 作用下， 以 乙醇 、 水 为溶剂， 反应 20.0h， 以77%的产率得到descladinose-4'-ethynylbenzylclarithromycin
  参考文献：
  名称：

  Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton

  摘要：

  Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDACs 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme's outer rim and the inhibitors' macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity.

  DOI：

  10.1021/jm100507q
• 作为产物：
  描述：

  克拉霉素 在 碘 、 sodium acetate 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 氯仿 、 二甲基亚砜 为溶剂， 反应 6.67h， 生成 3'-N-(desmethyl)-3'-N-(4-ethynylbenzyl)clarithromycin
  参考文献：
  名称：

  [EN] COMPOSITIONS AND METHODS FOR INHIBITING FIBROSIS, INFLAMMATION AND CANCER
  [FR] COMPOSITIONS ET MÉTHODES POUR INHIBER LA FIBROSE, L'INFLAMMATION ET LE CANCER

  摘要：

  本文提供基于大环化合物或其对映体、溶剂化物或其药学上可接受的盐。还提供包括上述化合物的药物组合物和药物，以及治疗纤维化、炎症性疾病和癌症的方法。

  公开号：

  WO2022146980A1

文献信息

• A structure–activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities
  作者：Subhasish Tapadar、Shaghayegh Fathi、Idris Raji、Wilson Omesiete、James R. Kornacki、Sandra C. Mwakwari、Masanori Miyata、Kazunori Mitsutake、Jian-Dong Li、Milan Mrksich、Adegboyega K. Oyelere

  DOI：10.1016/j.bmc.2015.10.045

  日期：2015.12

  Inhibition of the enzymatic activity of histone deacetylase (HDAC) is a promising therapeutic strategy for cancer treatment and several distinct small molecule histone deacetylase inhibitors (HDACi) have been reported. We have previously identified a new class of non-peptide macrocyclic HDACi derived from 14- and 15-membered macrolide skeletons. In these HDACi, the macrocyclic ring is linked to the zinc chelating hydroxamate moiety through a para-substituted aryl-triazole cap group. To further delineate the depth of the SAR of this class of HDACi, we have synthesized series of analogous compounds and investigated the influence of various substitution patterns on their HDAC inhibitory, anti-proliferative and anti-inflammatory activities. We identified compounds 25b and 38f with robust anti-proliferative activities and compound 26f (IC50 47.2 nM) with superior anti-inflammatory (IC50 88 nM) activity relative to SAHA. (C) 2015 Elsevier Ltd. All rights reserved.
• Non-Peptide Macrocyclic Histone Deacetylase Inhibitors
  作者：Adegboyega K. Oyelere、Po C. Chen、William Guerrant、Sandra C. Mwakwari、Rebecca Hood、Yunzhe Zhang、Yuhong Fan

  DOI：10.1021/jm801128g

  日期：2009.1.22

  Inhibition of histone deacetylase inhibitors (HDACi) hold great promise in cancer therapy because of their demonstrated ability to arrest proliferation of nearly all transformed cell types. Of the several structurally distinct small molecule HDACi reported, macrocyclic depsipeptides have the most complex recognition cap-group moieties and present an excellent opportunity for the modulation of the biological activities of HDACi. Unfortunately, the structure-activity relationship (SAR) studies for this class of compounds have been impaired largely because most macrocyclic HDACi known to date comprise complex peptide macrocycles. In addition to retaining the pharmacologically disadvantaged peptidyl backbone, they offer only limited opportunity for side chain modifications. Here, we report the discovery of a new class of macrocyclic HDAG based on the macrolide antibiotics skeletons. SAR studies revealed that these compounds displayed both linker-length and macrolide-type dependent HDAC inhibition activities with IC50 in the low nanomolar range. In addition, these non-peptide macrocyclic HDACi are more selective against HDACs 1 and 2 relative to HDAC 8, another class I HDAC isoform, and hence have subclass HDAC isoform selectivity.
• Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton
  作者：Sandra C. Mwakwari、William Guerrant、Vishal Patil、Shabana I. Khan、Babu L. Tekwani、Zachary A. Gurard-Levin、Milan Mrksich、Adegboyega K. Oyelere

  DOI：10.1021/jm100507q

  日期：2010.8.26

  Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDACs 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme's outer rim and the inhibitors' macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity.
• [EN] COMPOSITIONS AND METHODS FOR INHIBITING FIBROSIS, INFLAMMATION AND CANCER<br/>[FR] COMPOSITIONS ET MÉTHODES POUR INHIBER LA FIBROSE, L'INFLAMMATION ET LE CANCER
  申请人：GEORGIA TECH RES INST

  公开号：WO2022146980A1

  公开（公告）日：2022-07-07

  Provided herein are macrocycle-based compounds or diastereomers, solvate, or a pharmaceutically acceptable salt thereof. Also provided are pharmaceutical compositions and medicaments that include the compounds described herein as well as methods of treating fibrosis, inflammatory disease, and cancer.

  本文提供基于大环化合物或其对映体、溶剂化物或其药学上可接受的盐。还提供包括上述化合物的药物组合物和药物，以及治疗纤维化、炎症性疾病和癌症的方法。