4-[(4-azidophenyl)sulfonyl]-N-(tetrahydro-2H-pyran-2-yloxy)-tetrahydro-2H-pyran-4-carboxamide | 1314020-65-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-[(4-azidophenyl)sulfonyl]-N-(tetrahydro-2H-pyran-2-yloxy)-tetrahydro-2H-pyran-4-carboxamide
• 英文别名: 4-(4-azidophenyl)sulfonyl-N-(oxan-2-yloxy)oxane-4-carboxamide
• CAS: 1314020-65-9
• 化学式: C₁₇H₂₂N₄O₆S
• 分子量: 410.451
• InChiKey: GSNZKFFNRFRVJB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-[(4-azidophenyl)sulfonyl]-N-(tetrahydro-2H-pyran-2-yloxy)-tetrahydro-2H-pyran-4-carboxamide 在 盐酸 、 copper(ll) sulfate pentahydrate 、 sodium ascorbate 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 叔丁醇 为溶剂， 反应 2.0h， 生成 N-hydroxy-4-[(4-{4-[((phenylsulfonyl)carbamoylamino)methyl]-1H-1,2,3-triazole-1-yl}phenyl)sulfonyl]-tetrahydro-2H-pyran-4-carboxamide
  参考文献：
  名称：

  Potent “Clicked” MMP2 Inhibitors: Synthesis, Molecular Modeling and Biological Exploration

  摘要：

  介绍了一系列新型基质金属蛋白酶2（MMP2）抑制剂，这些抑制剂采用基于片段的药物设计方法进行设计。合成了一种包含叠氮基团和在α-砜α-四氢吡喃骨架中的已知羟肟酸锌结合基团的片段。水-LOGSY、STD和竞争性STD实验表明该片段与酶的活性部位结合。通过点击化学反应将叠氮基团与疏水炔烃连接，这些疏水炔烃被选为与MMP2的S1′亚单位选择性相互作用，正如设计的化合物的对接和分子动力学实验所示。最有力的化合物18和19对MMP2的IC50分别为1.4和0.3 nM，对MMP1和MMP7这两种具有浅S1′亚位点的金属蛋白酶几乎没有活性。化合物18还显示出对一些抗靶金属蛋白酶（如MMP8）有前景的选择性，对MMP14（IC50 = 65 nM）和MMP9（IC50 = 98 nM）的活性显著降低，这些MMP的特点是具有深S1′口袋，因此与MMP2更相似。

  DOI：

  10.1039/c0ob00852d
• 作为产物：
  描述：

  methyl 2-(4-nitrophenylthio)acetate 在 N-甲基吗啉 、 亚硝酸特丁酯 、 叠氮基三甲基硅烷 、 potassium peroxomonosulfate 、 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 20.0 ℃ 、413.7 kPa 条件下， 反应 33.0h， 生成 4-[(4-azidophenyl)sulfonyl]-N-(tetrahydro-2H-pyran-2-yloxy)-tetrahydro-2H-pyran-4-carboxamide
  参考文献：
  名称：

  Potent “Clicked” MMP2 Inhibitors: Synthesis, Molecular Modeling and Biological Exploration

  摘要：

  介绍了一系列新型基质金属蛋白酶2（MMP2）抑制剂，这些抑制剂采用基于片段的药物设计方法进行设计。合成了一种包含叠氮基团和在α-砜α-四氢吡喃骨架中的已知羟肟酸锌结合基团的片段。水-LOGSY、STD和竞争性STD实验表明该片段与酶的活性部位结合。通过点击化学反应将叠氮基团与疏水炔烃连接，这些疏水炔烃被选为与MMP2的S1′亚单位选择性相互作用，正如设计的化合物的对接和分子动力学实验所示。最有力的化合物18和19对MMP2的IC50分别为1.4和0.3 nM，对MMP1和MMP7这两种具有浅S1′亚位点的金属蛋白酶几乎没有活性。化合物18还显示出对一些抗靶金属蛋白酶（如MMP8）有前景的选择性，对MMP14（IC50 = 65 nM）和MMP9（IC50 = 98 nM）的活性显著降低，这些MMP的特点是具有深S1′口袋，因此与MMP2更相似。

  DOI：

  10.1039/c0ob00852d

文献信息

• From a MMP2/CK2 multitarget approach to the identification of potent and selective MMP13 inhibitors
  作者：Miryam Pastor、José María Zapico、Claire Coderch、Maciej Maslyk、Rostyslav Panchuk、Beatriz de Pascual-Teresa、Ana Ramos

  DOI：10.1039/c8ob02990c

  日期：——

  MMP2/CK2 dual targeting inhibitors. We have followed a rational drug design approach based on our experience in the selective inhibition of these two enzymes. We have successfully obtained highly active MMP2 (10, IC50 = 70 nM; 11, IC50 = 100 nM) and CK2 (16a, IC50 = 500 nM) inhibitors. However, structural fine tuning of these small molecules to simultaneously target both enzymes turned out to be an unattainable

  在本文中，我们描述了我们在寻找MMP2 / CK2双重靶向抑制剂方面的努力。我们根据选择性抑制这两种酶的经验，采用了合理的药物设计方法。我们已经成功获得了高活性的MMP2（10，IC 50 = 70 nM; 11，IC 50 = 100 nM）和CK2（16a，IC 50 = 500 nM）抑制剂。然而，对这些小分子进行结构微调以同时靶向两种酶被证明是无法实现的目标。出乎意料的是，我们很幸运地发现了新的选择性MMP13抑制剂（10，IC 50 = 3.7 nM和11，IC 50= 5.6 nM）的TBB衍生支架。这些化合物构成了进一步优化的有趣起点。
• Progress towards water-soluble triazole-based selective MMP-2 inhibitors
  作者：Benjamin Fabre、Kamila Filipiak、José María Zapico、Natalia Díaz、Rodrigo J. Carbajo、Anne K. Schott、María Paz Martínez-Alcázar、Dimas Suárez、Antonio Pineda-Lucena、Ana Ramos、Beatriz de Pascual-Teresa

  DOI：10.1039/c3ob41046c

  日期：——

  Water solubility is a key aspect that needs to be addressed to obtain drug-like compounds. In an effort to improve the water solubility of our recently reported nanomolar matrix metalloproteinase type 2 (MMP-2) inhibitors based on triazole-substituted hydroxamates, we synthesized a new series of α-sulfone, α-tetrahydropyran and α-piperidine, α-sulfone clicked hydroxamates and determined their inhibitory activities against both MMP-2 and MMP-9. The best results were found for 13e, a water-soluble compound that displays a low nanomolar activity against MMP-2 and is 26-fold less active against MMP-9. This finding allowed us to pursue in vitro permeability through the Caco-2 monolayer and opened the possibility of carrying out further preclinical investigations. Docking and MD simulations have been performed in order to rationalize the biological results. The inhibitory activity of this compound against a panel of ten MMPs was determined showing an interesting MMP-2/MMP-1, -8, and -14 selectivity profile. The cytotoxicity and anti-invasive activity of the compounds on highly metastatic human fibrosarcoma tumor cells (HT1080) were determined, showing, at 10 μM concentration, a decrease in cell invasiveness up to 80%.

  水溶性是获得类药物化合物需要解决的关键问题。为了提高我们近期报道的基于三唑取代的羟肟酸的纳摩尔级基质金属蛋白酶2型（MMP-2）抑制剂的水溶性，我们合成了一系列新的α-砜、α-四氢吡喃和α-哌啶、α-砜点击羟肟酸化合物，并测定了它们对MMP-2和MMP-9的抑制活性。最佳结果显示，化合物13e具有水溶性，对MMP-2表现出低纳摩尔活性，对MMP-9的活性降低了26倍。这一发现使我们能够进行Caco-2单层细胞的体外通透性研究，并开启了进一步临床前研究的可能性。为了合理化生物学结果，我们进行了对接和分子动力学（MD）模拟。测定了该化合物对十个MMP组分的抑制活性，显示了有趣的MMP-2/MMP-1、-8和-14选择性谱。测定了这些化合物对高转移性人纤维肉瘤肿瘤细胞（HT1080）的细胞毒性和抗侵袭活性，结果显示，在10 μM浓度下，细胞侵袭性降低了高达80%。
• Design and Synthesis of Water-Soluble and Potent MMP-13 Inhibitors with Activity in Human Osteosarcoma Cells
  作者：Jose Maria Zapico、Lourdes Acosta、Miryam Pastor、Loganathan Rangasamy、Laura Marquez-Cantudo、Claire Coderch、Irene Ortin、Maria Nicolau-Sanus、Leonor Puchades-Carrasco、Antonio Pineda-Lucena、Alejandro Majali-Martinez、Pilar Ramos、Beatriz de Pascual-Teresa、Ana Ramos

  DOI：10.3390/ijms22189976

  日期：——

  Osteoarthritis is a degenerative disease, often resulting in chronic joint pain and commonly affecting elderly people. Current treatments with anti-inflammatory drugs are palliative, making the discovery of new treatments necessary. The inhibition of matrix metalloproteinase MMP-13 is a validated strategy to prevent the progression of this common joint disorder. We recently described polybrominated benzotriazole derivatives with nanomolar inhibitory activity and a promising selectivity profile against this collagenase. In this work, we have extended the study in order to explore the influence of bromine atoms and the nature of the S1′ heterocyclic interacting moiety on the solubility/selectivity balance of this type of compound. Drug target interactions have been assessed through a combination of molecular modeling studies and NMR experiments. Compound 9a has been identified as a water-soluble and highly potent inhibitor with activity in MG-63 human osteosarcoma cells.

  骨关节炎是一种退行性疾病，常导致慢性关节疼痛，通常影响老年人。目前使用抗炎药物治疗是缓解性的，因此发现新的治疗方法是必要的。抑制基质金属蛋白酶MMP-13是预防这种常见关节疾病进展的一种验证策略。我们最近描述了具有纳摩尔抑制活性和有希望的选择性谱的多溴苯并三唑衍生物。在这项研究中，我们扩展了研究，以探索溴原子的影响以及S1'杂环相互作用基团的性质对这类化合物的溶解度/选择性平衡的影响。通过分子建模研究和NMR实验的结合评估了药物靶标相互作用。已确定9a化合物是一种水溶性和高效的抑制剂，在MG-63人类骨肉瘤细胞中具有活性。
• Potent “Clicked” MMP2 Inhibitors: Synthesis, Molecular Modeling and Biological Exploration
  作者：Jose María Zapico、Pilar Serra、Josune García-Sanmartín、Kamila Filipiak、Rodrigo J. Carbajo、Anne K. Schott、Antonio Pineda-Lucena、Alfredo Martínez、Sonsoles Martín-Santamaría、Beatriz de Pascual-Teresa、Ana Ramos

  DOI：10.1039/c0ob00852d

  日期：——

  A new series of MMP2 inhibitors is described, following a fragment-based drug design approach. One fragment containing an azide group and a well known hydroxamate Zinc Binding Group in a α-sulfone, α-tetrahydropyrane scaffold, has been synthesized. Water-LOGSY, STD and competition-STD experiments indicate that this fragment binds to the active site of the enzyme. A click chemistry reaction was used to connect the azide to lipophilic alkynes selected to interact selectively with the S1′ subunit of MMP2, as shown by docking and molecular dynamic experiments of the designed compounds. The most potent compounds 18 and 19 displayed an IC50 of 1.4 and 0.3 nM against MMP2 respectively, and showed negligible activity towards MMP1 and MMP7, two metalloproteinases which have a shallow S1′ subsite. Compound 18 also showed a promising selectivity profile against some antitarget metalloproteinases, such as MMP8, and considerably less activity against MMP14 (IC50 = 65 nM), and MMP9 (IC50 = 98 nM), other MMPs characterized by having a deep S1′ pocket and, therefore, more similar to MMP2.

  介绍了一系列新型基质金属蛋白酶2（MMP2）抑制剂，这些抑制剂采用基于片段的药物设计方法进行设计。合成了一种包含叠氮基团和在α-砜α-四氢吡喃骨架中的已知羟肟酸锌结合基团的片段。水-LOGSY、STD和竞争性STD实验表明该片段与酶的活性部位结合。通过点击化学反应将叠氮基团与疏水炔烃连接，这些疏水炔烃被选为与MMP2的S1′亚单位选择性相互作用，正如设计的化合物的对接和分子动力学实验所示。最有力的化合物18和19对MMP2的IC50分别为1.4和0.3 nM，对MMP1和MMP7这两种具有浅S1′亚位点的金属蛋白酶几乎没有活性。化合物18还显示出对一些抗靶金属蛋白酶（如MMP8）有前景的选择性，对MMP14（IC50 = 65 nM）和MMP9（IC50 = 98 nM）的活性显著降低，这些MMP的特点是具有深S1′口袋，因此与MMP2更相似。