(S)-5-((R)-2-((N-hydroxyformamido)methyl)hexanoyl)-N-(3-(pyridin-3-yl)phenyl)-5-azaspiro[2.4]heptane-6-carboxamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (S)-5-((R)-2-((N-hydroxyformamido)methyl)hexanoyl)-N-(3-(pyridin-3-yl)phenyl)-5-azaspiro[2.4]heptane-6-carboxamide
• 英文别名: (S)-5-((R)-2-((N-hydroxyformamido)methyl)hexylcarbonyl)-N-(3-(pyridin-3-yl)phenyl)-5-azaspiro[2.4] heptane-6-amide；(6S)-5-[(2R)-2-[[formyl(hydroxy)amino]methyl]hexanoyl]-N-(3-pyridin-3-ylphenyl)-5-azaspiro[2.4]heptane-6-carboxamide
• 化学式: C₂₆H₃₂N₄O₄
• 分子量: 464.564
• InChiKey: OACDTFQNNDEQMB-GGAORHGYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-氨基苯硼酸 在 N-甲基咪唑 、 盐酸 、 四(三苯基膦)钯 、 三异丙基硅烷 、 甲基磺酰氯 、 三氟乙酸 作用下， 以 甲醇 、 乙二醇二甲醚 、 乙醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.5h， 生成 (S)-5-((R)-2-((N-hydroxyformamido)methyl)hexanoyl)-N-(3-(pyridin-3-yl)phenyl)-5-azaspiro[2.4]heptane-6-carboxamide
  参考文献：
  名称：

  新型肽去甲酰基酶抑制剂的设计，合成和药代动力学评估

  摘要：

  筛选设计的小分子配体的对接方法导致鉴定了肽去甲酰基酶中螺旋环丙基PDF抑制剂的额外疏水结合的关键精氨酸残基，这为我们寻找更有效的PDF抑制剂以对抗可怕的抗生素耐药性提供了有用的工具。进行了进一步的合成修饰以优化酰胺化合物的效力。为了降低代谢敏感性并进而降低临床上观察到的有害代谢毒性，同时保持所需的抗菌活性，还研究了将唑类用作酰胺类生物等排体。化学合成完成后，通过体外抗菌活性测定法评估所有化合物，其中一些化合物还需进行体内大鼠药代动力学评估。N-甲酰基羟胺，尤其是生物等位唑，可以代表一类有前途的PDF抑制剂。

  DOI：

  10.1016/j.bmcl.2016.05.077

文献信息

• SPIRO THREE-MEMBERED RING, SPIRO FIVE-MEMBERED RING PEPTIDE DEFORMYLASE INHIBITOR AND USE THEREOF IN ANTIBACTERIA AND ANTI-TUMOUR.
  申请人：Rudong Ruien Pharmaceutical Technology Co., Ltd.

  公开号：EP3483155A1

  公开（公告）日：2019-05-15

  Disclosed are the anti-bacterial activity and the anti-tumor activity of a class of new spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor. The spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor of the present invention, as a class of new anti-bacterial agent, are effective against many antibiotic-resistant Gram-positive strains by inhibiting the activity of the peptide deformylase required in the synthesis of bacterial proteins, and do not affect the synthetic process of the main proteins of the human body, thus selectively killing bacteria. The spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor of the present invention, as a class of new anti-bacterial agent, can affect the energy balance of the cancer cells through inhibiting the peptide deformylase of the mitochondria in the cells, so that the mitochondrial membrane is depolarized, ATP is exhausted and cell apoptosis is promoted, and has good inhibitory activities on many cancer cell strains such as colorectal cancer, leukemia, lung cancer, gastric cancer, cervical cancer, breast cancer, prostatic cancer, liver cancer and osteosarcoma at relatively lower concentrations.

  本发明公开了一类新型螺三元环和螺五元环肽变形酶抑制剂的抗菌活性和抗肿瘤活性。本发明的螺三元环和螺五元环肽基变形酶抑制剂作为一类新型抗菌剂，通过抑制细菌蛋白质合成过程中所需的肽基变形酶的活性，对多种抗生素耐药的革兰氏阳性菌株有效，且不影响人体主要蛋白质的合成过程，从而选择性地杀灭细菌。本发明的螺三元环、螺五元环肽变形酶抑制剂作为一类新型抗菌剂，通过抑制细胞内线粒体的肽变形酶，使线粒体膜去极化，从而影响癌细胞的能量平衡、在相对较低的浓度下，对大肠癌、白血病、肺癌、胃癌、宫颈癌、乳腺癌、前列腺癌、肝癌和骨肉瘤等多种癌细胞株具有良好的抑制活性。
• Spiro three-membered ring, spiro five-membered ring peptide deformylase inhibitor and use thereof in antibacteria and anti-tumor
  申请人：Rudong Ruien Pharmaceutical Technology Co. Ltd

  公开号：US10738028B2

  公开（公告）日：2020-08-11

  Disclosed are the anti-bacterial activity and the anti-tumor activity of a class of new spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor. The spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor of the present invention, as a class of new anti-bacterial agent, are effective against many antibiotic-resistant Gram-positive strains by inhibiting the activity of the peptide deformylase required in the synthesis of bacterial proteins, and do not affect the synthetic process of the main proteins of the human body, thus selectively killing bacteria. The spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor of the present invention, as a class of new anti-bacterial agent, can affect the energy balance of the cancer cells through inhibiting the peptide deformylase of the mitochondria in the cells, so that the mitochondrial membrane is depolarized, ATP is exhausted and cell apoptosis is promoted, and has good inhibitory activities on many cancer cell strains such as colorectal cancer, leukemia, lung cancer, gastric cancer, cervical cancer, breast cancer, prostatic cancer, liver cancer and osteosarcoma at relatively lower concentrations. The structure of exemplary invention spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitors are represented by one or more of:

  本发明公开了一类新型螺三元环和螺五元环肽变形酶抑制剂的抗菌活性和抗肿瘤活性。本发明的螺三元环和螺五元环肽基变形酶抑制剂作为一类新型抗菌剂，通过抑制细菌蛋白质合成过程中所需的肽基变形酶的活性，对多种抗生素耐药的革兰氏阳性菌株有效，且不影响人体主要蛋白质的合成过程，从而选择性地杀灭细菌。本发明的螺三元环、螺五元环肽变形酶抑制剂作为一类新型抗菌剂，通过抑制细胞内线粒体的肽变形酶，使线粒体膜去极化，从而影响癌细胞的能量平衡、在相对较低的浓度下，对大肠癌、白血病、肺癌、胃癌、宫颈癌、乳腺癌、前列腺癌、肝癌、骨肉瘤等多种癌细胞株具有良好的抑制活性。示例性发明螺三元环和螺五元环肽变形酶抑制剂的结构由以下一种或多种表示：
• [EN] SPIRO THREE-MEMBERED RING, SPIRO FIVE-MEMBERED RING PEPTIDE DEFORMYLASE INHIBITOR AND USE THEREOF IN ANTIBACTERIA AND ANTI-TUMOUR.<br/>[FR] NOYAU SPIRO À TROIS CHAÎNONS, INHIBITEUR DE PEPTIDE DÉFORMYLASE À NOYAU SPIRO À CINQ CHAÎNONS ET SON UTILISATION DANS DES AGENTS ANTI-BACTÉRIENS ET ANTI-TUMORAUX<br/>[ZH] 螺三元环、螺五元环类肽脱甲酰基酶抑制剂及其在抗菌和抗肿瘤中的应用
  申请人：RUDONG RUIEN PHARMACEUTICAL TECH CO LTD

  公开号：WO2017193924A1

  公开（公告）日：2017-11-16

  本发明公开了一类新型的含螺三元环、螺五元环类肽脱甲酰基酶抑制剂的抗菌活性和抗肿瘤活性。本发明的含螺三元环、螺五元环类螺环类肽脱甲酰基酶抑制剂可作为一类新型的抗菌剂，通过抑制细菌蛋白质合成中所需肽脱甲酰基酶的活性对多种抗生素耐药的革兰氏阳性菌菌株都有效，且不影响人体的主要蛋白质合成过程，从而选择性杀死细菌；本发明的含螺三元环、螺五元环类螺环类肽脱甲酰基酶抑制剂还可作为一类新型的抗癌药物，通过抑制癌症细胞线粒体中的肽脱甲酰基酶，可以影响细胞的能量平衡：从而使得线粒体膜去极化，ATP耗竭和促使细胞凋亡，在较低浓度下对多种癌细胞菌株如结直肠癌、白血病、肺癌、胃癌、宫颈癌、乳腺癌、前列腺癌、肝癌和骨肉瘤等具有较好的抑制活性。
• SPIRO THREE-MEMBERED RING, SPIRO FIVE-MEMBERED RING PEPTIDE DEFORMYLASE INHIBITOR AND USE THEREOF IN ANTIBACTERIA AND ANTI-TUMOR
  申请人：Rudong Ruien Pharmaceutical Technology Co.Ltd

  公开号：US20190194165A1

  公开（公告）日：2019-06-27

  Disclosed are the anti-bacterial activity and the anti-tumor activity of a class of new spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor. The spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor of the present invention, as a class of new anti-bacterial agent, are effective against many antibiotic-resistant Gram-positive strains by inhibiting the activity of the peptide deformylase required in the synthesis of bacterial proteins, and do not affect the synthetic process of the main proteins of the human body, thus selectively killing bacteria. The spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitor of the present invention, as a class of new anti-bacterial agent, can affect the energy balance of the cancer cells through inhibiting the peptide deformylase of the mitochondria in the cells, so that the mitochondrial membrane is depolarized, ATP is exhausted and cell apoptosis is promoted, and has good inhibitory activities on many cancer cell strains such as colorectal cancer, leukemia, lung cancer, gastric cancer, cervical cancer, breast cancer, prostatic cancer, liver cancer and osteosarcoma at relatively lower concentrations.