[(1S,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] (2S)-2-[methyl(3-sulfanylpropanoyl)amino]propanoate

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: [(1S,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] (2S)-2-[methyl(3-sulfanylpropanoyl)amino]propanoate
• 化学式: C₃₅H₄₈ClN₃O₁₀S
• 分子量: 738.3
• InChiKey: ANZJBCHSOXCCRQ-NSGBNUDBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  50
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  158
• 氢给体数：
  3
• 氢受体数：
  11

文献信息

• [EN] METHODS FOR MAKING CONJUGATES FROM DISULFIDE-CONTAINING PROTEINS<br/>[FR] PROCÉDÉS POUR LA FABRICATION DE CONJUGUÉS À PARTIR DE PROTÉINES CONTENANT DU DISULFURE
  申请人：NOVARTIS AG

  公开号：WO2014083505A1

  公开（公告）日：2014-06-05

  The invention provides methods to prepare protein conjugates from proteins having at least two cysteines. In one embodiment, a protein with a disulfide linkage is reduced to provide two free cysteines for reaction with a 1,3-dihaloacetone or similar reactant, linking the sulfur atoms of the two cysteines together. The ketone inserted between the sulfur atoms is then used to form a Schiff base to an aminated payload molecule, thus conjugating the protein to a payload. In another embodiment, two cysteine residues are tied together by reaction with a 1,3-dihaloacetone or similar reactant. The linkage between the sulfur atoms in each case holds the protein or peptide in a constrained conformation, while also providing a convenient place for attaching a payload with good specificity and efficiency.

  该发明提供了一种从至少含有两个半胱氨酸的蛋白质制备蛋白质共轭物的方法。在一个实施例中，将含有二硫键的蛋白质还原，以提供两个自由的半胱氨酸，用于与1,3-二卤代丙酮或类似试剂发生反应，将两个半胱氨酸的硫原子连接在一起。然后，插入在硫原子之间的酮基被用来与氨基负载分子形成席夫碱，从而将蛋白质与负载结合起来。在另一个实施例中，通过与1,3-二卤代丙酮或类似试剂发生反应，将两个半胱氨酸残基连接在一起。在每种情况下，硫原子之间的连接使蛋白质或肽以受限构象存在，同时还提供了一个方便的位置，用于连接具有良好特异性和效率的负载。
• [EN] DRUG-PROTEIN CONJUGATES<br/>[FR] CONJUGUÉS MÉDICAMENT-PROTÉINE
  申请人：POLYTHERICS LTD

  公开号：WO2014064423A1

  公开（公告）日：2014-05-01

  Specific conjugates containing auristatins and a binding protein or peptide, and processes for making them, are described. The conjugates use specific linker technology which gives advantages over known antibody-drug conjugates. Also described are specific conjugates of drugs and a binding protein or peptide in which more than one copy of the drug is present.

  包含奥利司他汀和结合蛋白或肽的特定共轭物以及制备它们的过程被描述。这些共轭物使用特定的连接技术，相比已知的抗体药物共轭物具有优势。还描述了药物和结合蛋白或肽的特定共轭物，其中药物的副本超过一个。
• METHODS FOR OXIME CONJUGATION TO KETONE-MODIFIED POLYPEPTIDES
  申请人：Hu Qi-Ying

  公开号：US20150150998A1

  公开（公告）日：2015-06-04

  The invention provides improved methods to prepare protein conjugates from a ketone-modified protein. In one embodiment, the protein is prepared by linking two free cysteines by reaction with a 1,3-dihaloacetone or similar ketone-containing reactant, linking the sulfur atoms of the two cysteines together. The ketone inserted between the sulfur atoms is then used to form an oxime, thus conjugating the protein to a payload. In another embodiment, two cysteine residues are tied together by reaction with a 1,3-dihaloacetone or similar reactant, and the new ketone is used to form an oxime with a suitable payload molecule, thus conjugating the protein to a payload. The method provides improved reaction conditions for the oxime formation, whereby higher yields and improved product homogeneity are achieved.

  本发明提供了改进的方法，用于从酮改性蛋白质制备蛋白质共轭物。在一种实施例中，通过使用1,3-二卤代酮或类似含酮反应物将两个游离半胱氨酸连接起来，将两个半胱氨酸的硫原子连接在一起，从而制备蛋白质。然后使用插入在硫原子之间的酮来形成肟，从而将蛋白质与有效载荷共轭。在另一种实施例中，通过使用1,3-二卤代酮或类似反应物将两个半胱氨酸残基连接在一起，并使用新的酮将肟与合适的有效载荷分子结合，从而将蛋白质与有效载荷共轭。该方法提供了改进的肟形成反应条件，从而实现更高的产率和更好的产物均一性。
• Methods for making conjugates from disulfide-containing proteins
  申请人：Hu Qi-Ying

  公开号：US10022256B2

  公开（公告）日：2018-07-17

  The invention provides methods to prepare protein conjugates from proteins having at least two cysteines. In one embodiment, a protein with a disulfide linkage is reduced to provide two free cysteines for reaction with a 1,3-dihaloacetone or similar reactant, linking the sulfur atoms of the two cysteines together. The ketone inserted between the sulfur atoms is then used to form a Schiff base to an aminated payload molecule, thus conjugating the protein to a payload. In another embodiment, two cysteine residues are tied together by reaction with a 1,3-dihaloacetone or similar reactant. The linkage between the sulfur atoms in each case holds the protein or peptide in a constrained conformation, while also providing a convenient place for attaching a payload with good specificity and efficiency.

  本发明提供了用至少有两个半胱氨酸的蛋白质制备蛋白质共轭物的方法。在一个实施方案中，将具有二硫连接的蛋白质还原，以提供两个游离半胱氨酸，与 1,3-二卤丙酮或类似反应物反应，将两个半胱氨酸的硫原子连接在一起。然后，插入硫原子间的酮与胺化的有效载荷分子形成希夫碱，从而将蛋白质与有效载荷连接起来。在另一个实施方案中，两个半胱氨酸残基通过与 1,3-二卤丙酮或类似反应物反应连接在一起。在每种情况下，硫原子之间的连接都能使蛋白质或肽保持一定的构象，同时还能提供一个方便的位置，以良好的特异性和效率连接有效载荷。
• Methods for oxime conjugation to ketone-modified polypeptides
  申请人：Hu Qi-Ying

  公开号：US10172948B2

  公开（公告）日：2019-01-08

  The invention provides improved methods to prepare protein conjugates from a ketone-modified protein. In one embodiment, the protein is prepared by linking two free cysteines by reaction with a 1,3-dihaloacetone or similar ketone-containing reactant, linking the sulfur atoms of the two cysteines together. The ketone inserted between the sulfur atoms is then used to form an oxime, thus conjugating the protein to a payload. In another embodiment, two cysteine residues are tied together by reaction with a 1,3-dihaloacetone or similar reactant, and the new ketone is used to form an oxime with a suitable payload molecule, thus conjugating the protein to a payload. The method provides improved reaction conditions for the oxime formation, whereby higher yields and improved product homogeneity are achieved.

  本发明提供了用酮修饰蛋白质制备蛋白质共轭物的改进方法。在一个实施方案中，制备蛋白质的方法是通过与 1,3-二卤丙酮或类似的含酮反应物反应，将两个游离半胱氨酸的硫原子连接在一起。然后，插入硫原子间的酮被用来形成肟，从而将蛋白质与有效载荷连接起来。在另一个实施方案中，通过与 1,3-二卤丙酮或类似反应物反应，将两个半胱氨酸残基连接在一起，然后使用新的酮与合适的有效载荷分子形成肟，从而将蛋白质与有效载荷连接在一起。该方法为肟的形成提供了更好的反应条件，从而获得更高的产率和更好的产品均匀性。