5-azido-O-tritylpentahydroxamate | 1360130-72-8

• 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: 5-azido-O-tritylpentahydroxamate
• 英文别名: O-trityl 5-azidopentahydroxamate
• CAS: 1360130-72-8
• 化学式: C₂₄H₂₄N₄O₂
• 分子量: 400.48
• InChiKey: GMTMGTLZTDEWTD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.51
• 重原子数：
  30.0
• 可旋转键数：
  10.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  87.09
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  5-azido-O-tritylpentahydroxamate 在 三异丙基硅烷 、 三苯基膦 、 三氟乙酸 、 四甲基胍 作用下， 以 四氢呋喃 、 二甲基亚砜 为溶剂， 反应 4.0h， 生成 4-(((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl)amino)-N-(5-(hydroxyamino)-5-oxopentyl)benzamide
  参考文献：
  名称：

  Design and structure activity relationship of tumor-homing histone deacetylase inhibitors conjugated to folic and pteroic acids

  摘要：

  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.

  DOI：

  10.1016/j.ejmech.2015.04.014
• 作为产物：
  描述：

  5-溴戊酸 在 N-甲基吗啉 、 sodium azide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 5-azido-O-tritylpentahydroxamate
  参考文献：
  名称：

  Dual-acting histone deacetylase-topoisomerase I inhibitors

  摘要：

  Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands that can modulate multiple targets while avoiding the toxicity of a single-targeted agent. Two attractive targets, histone deacetylase (HDAC) and topoisomerase I (Topo I), are cellular modulators that can broadly arrest cancer proliferation through a range of downstream effects. Both are clinically validated targets with multiple inhibitors in therapeutic use. We describe herein the design and synthesis of dual-acting histone deacetylase-topoisomerase I inhibitors. We also show that these dual-acting agents retain activity against HDAC and Topo I, and potently arrest cancer proliferation. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2013.03.108

文献信息

• [EN] HISTONE DEACETYLASE (HDAC) INHIBITORS TARGETING PROSTATE TUMORS AND METHODS OF MAKING AND USING THEREOF<br/>[FR] INHIBITEURS D'HISTONE DÉSACÉTYLASE (HDAC) CIBLANT LES TUMEURS DE LA PROSTATE ET PROCÉDÉS POUR LES PRÉPARER ET LES UTILISER
  申请人：GEORGIA TECH RES INST

  公开号：WO2012050868A1

  公开（公告）日：2012-04-19

  Compounds of Formula (I), and methods of making and using thereof, are described herein; wherein AR is an aryl group, ZBG is a Zinc Binding Group, and other substituents are as defined herein. The compounds can be administered as a pharmaceutically acceptable salt, prodrug, or solvate. The compounds may be useful to treat and/or prevent hyperproliferative disorders which may include hormone sensitive and hormone refractory prostate cancers. The compounds can be formulated with a pharmaceutically acceptable carrier and, optionally one or more pharmaceutically acceptable excipients, for enteral or parenteral administration.

  本文描述了Formula (I)的化合物及其制备和使用方法；其中AR是芳基基团，ZBG是锌结合基团，其他取代基如本文所定义。这些化合物可以作为药学上可接受的盐、前药或溶剂形式进行给药。这些化合物可能有助于治疗和/或预防可以包括激素敏感和激素耐药的前列腺癌等高增殖性疾病。这些化合物可以与药学上可接受的载体以及选择性地与一个或多个药学上可接受的赋形剂配制，用于肠道或静脉注射给药。
• Designing Dual Transglutaminase 2/Histone Deacetylase Inhibitors Effective at Halting Neuronal Death
  作者：Manuela Basso、Huan Huan Chen、Debasmita Tripathy、Mariarosaria Conte、Kim Y. P. Apperley、Angela De Simone、Jeffrey W. Keillor、Rajiv Ratan、Angela Nebbioso、Federica Sarno、Lucia Altucci、Andrea Milelli

  DOI：10.1002/cmdc.201700601

  日期：2018.2.6

  Herein we report that combined inhibition of transglutaminase 2 (TG2) and histone deacetylases (HDACs) synergistically protects against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2–HDAC binding agents. Compound 3 [(E)‐N‐hydroxy‐5‐(3‐(4‐(3‐oxo‐3‐(pyridin‐3‐yl)prop‐1‐en‐1‐yl)phenyl)thioureido)pentanamide] emerged as the most interesting

  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。
• 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.