(3'-N-(4-ethynylbenzyl))azithromycin | 1093856-81-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (3'-N-(4-ethynylbenzyl))azithromycin
• 英文别名: 4'-ethynylbenzylazithromycin；(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-[(2S,3R,4S,6R)-4-[(4-ethynylphenyl)methyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one
• CAS: 1093856-81-5
• 化学式: C₄₆H₇₆N₂O₁₂
• 分子量: 849.116
• InChiKey: ACGCZFOPBKZCTP-SYZJSEJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  60
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  180
• 氢给体数：
  5
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  (3'-N-(4-ethynylbenzyl))azithromycin 在 N-氯代丁二酰亚胺 、 二甲基硫 、 sodium hydride 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 48.08h， 生成 ((4"-epoxy)-3'-O-acetyl)-4'-N-(4-ethynylbenzyl)azithromycin
  参考文献：
  名称：

  A structure–activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities

  摘要：

  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.

  DOI：

  10.1016/j.bmc.2015.10.045
• 作为产物：
  描述：

  阿奇霉素 在 碘 、 sodium acetate 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 水 、 二甲基亚砜 为溶剂， 反应 6.84h， 生成 (3'-N-(4-ethynylbenzyl))azithromycin
  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

• Liver-Targeting Class I Selective Histone Deacetylase Inhibitors Potently Suppress Hepatocellular Tumor Growth as Standalone Agents
  作者：Subhasish Tapadar、Shaghayegh Fathi、Bocheng Wu、Carrie Q. Sun、Idris Raji、Samuel G. Moore、Rebecca S. Arnold、David A. Gaul、John A. Petros、Adegboyega K. Oyelere

  DOI：10.3390/cancers12113095

  日期：——

  therapy strategy. However, current HDAC inhibitors (HDACi) have elicited limited therapeutic benefit against solid tumors. Here, we disclosed a class of HDACi that are selective for sub-class I HDACs and preferentially accumulate within the normal liver tissue and orthotopically implanted liver tumors. We observed that these compounds possess exquisite on-target effects evidenced by their induction of dose-dependent

  简单总结 肝癌是全球癌症死亡的主要原因之一。当前肝癌（包括占所有病例 80% 以上的肝细胞癌 (HCC)）的治疗选择对晚期疾病患者的益处有限。 HCC 是由遗传和表观遗传改变引起的，包括基因沉默染色质组蛋白低乙酰化。本研究的目的是探讨肝组织靶向 HDAC 抑制剂 (HDACi) 作为一类新型抗 HCC 药物的潜在效用。我们发现，一类基于大环内酯的 HDACi 对 I 亚类 HDAC 具有选择性，优先在肝组织中积累，并在 HCC 原位模型中强烈抑制肿瘤生长。这些化合物的肝脏组织选择性积累特性使它们比目前大多数 HDACi（包括目前临床使用的 HDACi）具有独特的优势。摘要 表观遗传调控功能障碍在肿瘤的发生和进展中发挥着关键作用。组蛋白脱乙酰酶 (HDAC) 和组蛋白乙酰转移酶 (HAT) 是功能上相反的表观遗传调节因子，控制肿瘤抑制基因的表达状态。 HDAC 活性上调在恶性肿瘤中占主导地位
• NON-PEPTIDE MACROCYCLIC HISTONE DEACETYLASE (HDAC) INHIBITORS AND METHODS OF MAKING AND USING THEREOF
  申请人：Oyelere Adegboyega

  公开号：US20120329741A1

  公开（公告）日：2012-12-27

  Compounds of Formula I or II, and methods of making and using thereof, are described herein. M represents a macrolide subunit, E is a C 1-6 group, optionally containing one or more heteroatoms, D is an alkyl or aryl group, A is a linking group connected to D, B is an alkyl, alkylaryl or alkylheteroaryl spacer group, ZBG is a Zinc Binding Group, R 1 , R 2 and R 4 are independently are selected from hydrogen, a C1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 alkanoate group, a C 2-6 carbamate group, a C 2-6 carbonate group, a C 2-6 carbamate group, or a C 2-6 thiocarbamate group, R 3 is hydrogen or —OR 5 , R 5 is selected from a group consisting of Hydrogen, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, C 1-6 alkanoate group, C 2-6 carbamate group, C 2-6 carbonate group, C 2-6 carbamate group, or C 2-6 thiocarbamate group.

  本文描述了I或II式化合物及其制备和使用方法。其中，M代表大环内酯亚基，E为C1-6基团，可选含有一个或多个杂原子，D为烷基或芳基基团，A为连接到D的连接基团，B为烷基、烷基芳基或烷基杂芳基间隔基团，ZBG为锌结合基团，R1、R2和R4独立地选择自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷酸酯基、C2-6氨基甲酸酯基、C2-6碳酸酯基、C2-6氨基甲酰基或C2-6硫代氨基甲酰基，R3为氢或-OR5，R5选择自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷酸酯基、C2-6氨基甲酸酯基、C2-6碳酸酯基、C2-6氨基甲酰基或C2-6硫代氨基甲酰基。
• 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.
• US8871728B2
  申请人：——

  公开号：US8871728B2

  公开（公告）日：2014-10-28
• 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.