6-azido-O-tritylhexahydroxamate | 1236149-35-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: 6-azido-O-tritylhexahydroxamate
• 英文别名: 6-azido-N-(trityloxy)hexanamide；O-trityl 6-azidohexahydroxamate；6-azido-N-trityloxyhexanamide
• CAS: 1236149-35-1
• 化学式: C₂₅H₂₆N₄O₂
• 分子量: 414.507
• InChiKey: YSLRZKCQUBWXCQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  31
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  52.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-azido-O-tritylhexahydroxamate 在 三乙基硅烷 、 水 、 三乙胺 、 三苯基膦 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 (E)-N-hydroxy-6-(3-(4-(3-oxo-3-(pyridin-3-yl)prop-1-en-1-yl)phenyl)thioureido)hexanamide
  参考文献：
  名称：

  设计有效阻止神经元死亡的双重转谷氨酰胺酶2 /组蛋白脱乙酰基酶抑制剂

  摘要：

  近年来，已经有一个明确的共识，即通过同时调节不同的靶标可以更好地治疗神经退行性疾病。本文中我们报道转谷氨酰胺酶2（TG2）和组蛋白脱乙酰基酶（HDACs）的组合抑制协同保护免受谷氨酸介导的毒性刺激。基于这些发现，我们设计并合成了一系列新颖的双重TG2-HDAC结合剂。化合物3 [（E）‐ N‐羟基‐5‐（3‐（4‐（3‐oxo‐3‐（吡啶基‐3‐基）丙-1-烯‐基‐苯基）苯硫脲基）戊酰胺]出现了作为该系列中最有趣的，能够抑制TG2和HDAC的在体外（TG2 IC 50 = 13.3±1.5μ米，HDAC1 IC 50 = 3.38±0.14μ米，HDAC6 IC 50 = 4.10±0.13μ米），并在基于细胞的测定。此外，化合物3不施加在皮层神经元的任何毒性作用可达50μ米，并保护神经元免于由谷氨酸（5米诱导毒性损伤米）与EC 50为3.7±0.5μ值米。

  DOI：

  10.1002/cmdc.201700601

文献信息

• Design, synthesis and evaluation of antiproliferative activity of melanoma-targeted histone deacetylase inhibitors
  作者：Idris Raji、Kabir Ahluwalia、Adegboyega K. Oyelere

  DOI：10.1016/j.bmcl.2017.01.044

  日期：2017.2

  The clinical validation of histone deacetylase inhibition as a cancer therapeutic modality has stimulated interest in the development of new generation of potent and tumor selective histone deacetylase inhibitors (HDACi). With the goal of selective delivery of the HDACi to melanoma cells, we incorporated the benzamide, a high affinity melanin-binding template, into the design of HDACi to generate a new

  组蛋白脱乙酰基酶抑制作为一种癌症治疗方法的临床验证激发了人们对新一代有效和肿瘤选择性组蛋白脱乙酰基酶抑制剂（HDACi）的开发兴趣。为了选择性地将HDACi递送至黑素瘤细胞，我们将苯甲酰胺（一种高亲和力的黑色素结合模板）整合到HDACi的设计中，以生成一系列新的化合物10a-b和11a-b，它们对HDAC1和HDAC6。但是，相对于未靶向的HDACi，这些化合物的抗增殖活性减弱。化合物14提供了另一种策略，一种带有苯甲酰胺模板的前药，该模板通过不稳定键与基于异羟肟酸酯的HDACi连接。这种前药化合物显示出有希望的抗增殖活性，值得进一步研究。
• Non-Peptide Macrocyclic Histone Deacetylase (HDAC) Inhibitors and Methods of Making and Using Thereof
  申请人：Oyelere Adegboyega

  公开号：US20100197622A1

  公开（公告）日：2010-08-05

  Compounds of Formula I or II, and methods of making and using thereof, are described herein. M represents a macrolide subunit, n 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 hgroup, 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.

  本文描述了公式I或II的化合物，以及制备和使用它们的方法。其中，M代表大环内酯亚基，n是C1-6基团，可选地含有一个或多个杂原子，D是烷基或芳基基团，A是连接到D的连接基团，B是烷基、烷基芳基或烷基杂芳基间隔基团，ZBG是锌结合基团，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氨基甲酸酯基或C2-6硫代氨基甲酸酯基，R3是氢或-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氨基甲酸酯基或C2-6硫代氨基甲酸酯基的一组。
• Design and structure activity relationship of tumor-homing histone deacetylase inhibitors conjugated to folic and pteroic acids
  作者：Quaovi H. Sodji、James R. Kornacki、John F. McDonald、Milan Mrksich、Adegboyega K. Oyelere

  DOI：10.1016/j.ejmech.2015.04.014

  日期：2015.5

  Histone deacetylase (HDAC) inhibition has recently emerged as a novel therapeutic approach for the treatment of various pathological conditions including cancer. Currently, two HDAC inhibitors (HDACi) - Vorinostat and Romidepsin - have been approved for the treatment of cutaneous T-cell lymphoma. However, HDACi remain ineffective against solid tumors and are associated with adverse events including cardiotoxicity. Targeted delivery may enhance the therapeutic indices of HDACi and enable them to be efficacious against solid tumors. We showed herein that morphing of folic and pteroic acids into the surface recognition group of HDACi results in hydroxamate and benzamide HDACi which derived tumor homing by targeting folate receptor (FR), a receptor commonly overexpressed in solid tumors. We observed a correlation between the potency of HDAC1 inhibition and cytotoxicity as only the potent pteroate hydroxamates, 11d and 11e, displayed antiproliferative activity against two representative FR-expression cancer cells. Our observation further supports the previous results which suggest that for a drug to be successfully targeted using the FR, it must be extremely potent against its primary target as the FR has a low delivery efficiency. Published by Elsevier Masson SAS.
• Dual Targeting of Histone Deacetylase and Topoisomerase II with Novel Bifunctional Inhibitors
  作者：William Guerrant、Vishal Patil、Joshua C. Canzoneri、Adegboyega K. Oyelere

  DOI：10.1021/jm200799p

  日期：2012.2.23

  Strategies to ameliorate the flaws of current chemotherapeutic agents, while maintaining potent anticancer activity, are of particular interest. Agents which can modulate multiple targets may have superior utility and fewer side effects than current single-target drugs. To explore the prospect in cancer therapy of a bivalent agent that combines two complementary chemo-active groups within a single molecular architecture, we have synthesized dual-acting histone deacetylase and topoisomerase II inhibitors. These dual-acting agents are derived from suberoylanilide hydroxamic acid (SAHA) and anthracycline daunorubicin, prototypical histone deacetylase (HDAC) and topoisomerase II (Topo II) inhibitors, respectively. We report herein that these agents present the signatures of inhibition of HDAC and Topo II in both cell-free and whole-cell assays. Moreover, these agents potently inhibit the proliferation of representative cancer cell lines.
• Histone Deacetylase Inhibitors Equipped with Estrogen Receptor Modulation Activity
  作者：Berkley E. Gryder、Michael K. Rood、Kenyetta A. Johnson、Vishal Patil、Eric D. Raftery、Li-Pan D. Yao、Marcie Rice、Bahareh Azizi、Donald F. Doyle、Adegboyega K. Oyelere

  DOI：10.1021/jm400467w

  日期：2013.7.25

  We describe a set of novel histone deacetylase inhibitors (HDACi) equipped with either an antagonist or an agonist of the estrogen receptor (ER) to confer selective activity against breast cancers. These bifunctional compounds potently inhibit HDAC at nanomolar concentrations and either agonize or antagonize ER alpha and ER beta. The ER antagonist activities of tamoxifen-HDACi conjugates (Tam-HDACi) are nearly identical to those of tamoxifen. Conversely, ethynyl-estradiol-HDACi conjugates (EED-HDACi) have attenuated ER agonist activities relative to the parent ethynyl-estradiol. In silico docking analysis provides structural basis for the trends of ER agonism/antagonism and ER subtype selectivity. Excitingly, lead Tam-HDACi conjugates show anticancer activity that is selectively more potent against MCF-7 (ER alpha positive breast cancer) compared to MDA-MB-231 (triple negative breast cancer), DU145 (prostate cancer), or Vero (noncancerous cell line). This dual-targeting approach illustrates the utility of designing small molecules with an emphasis on cell-type selectivity, not merely improved potency, working toward a higher therapeutic index at the earliest stages of drug development.