N²'-deacetyl-N²'-(3-methylthio-1-oxopropyl)maytansine | 912569-84-7

• 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: N²'-deacetyl-N²'-(3-methylthio-1-oxopropyl)maytansine
• 英文别名: N2'-deacetyl-N2'-(3-methylthio-1-oxopropyl)-maytansine；S-methyl DM1；[(1S,2R,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-methylsulfanylpropanoyl)amino]propanoate
• CAS: 912569-84-7
• 化学式: C₃₆H₅₀ClN₃O₁₀S
• 分子量: 752.326
• InChiKey: PLYHSTGTQYPYMT-JLZGXKMHSA-N

物化性质

• 熔点：
  >152°C (dec.)
• 沸点：
  936.9±65.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  51
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  182
• 氢给体数：
  2
• 氢受体数：
  11

安全信息

• 储存条件：
  存储条件：2-8°C，密封保存，干燥环境。

制备方法与用途

生物活性

S-methyl DM1 是一种美登素 (Maytansine) 的硫代甲基衍生物。其 Kd 值为 0.93 μM，结合微管蛋白并抑制微管聚合。S-methyl DM1 可以有效抑制微管动态不稳定性，并具有抗癌作用。

靶点

美登素类（Maytansinoids）

体外研究

S-methyl DM1 是通过与含巯基的美登素 DM1 聚合而成的抗体-美登素缀合物的主要细胞或肝代谢产物。其抑制微管组装半最大浓度为 4 μM，在 100 nM 浓度下，S-methyl-DM1（84%）比 Maytansine（45%）更强烈地抑制动态不稳定性和 37 高亲和力结合位点的放射性标记 S-methyl-DM1 绑定到微管上（Kd 值为 0.1 μM）。在 MCF7 细胞中，S-methyl DM1 对细胞增殖的抑制浓度依赖曲线呈 S 形。在 200 pM 浓度下几乎没有抑制作用，在 3 nM 浓度时达到最大抑制效果。与 Maytansine（IC50 值为 710 pM）相比，S-methyl DM1 的 IC50 值为 330 pM 更具效力。

在 MCF7 细胞中，S-methyl DM1 引起的最大 G2/M 期细胞积累为 80%，而对照组仅为 30%。

反应信息

• 作为反应物：
  描述：

  N²'-deacetyl-N²'-(3-methylthio-1-oxopropyl)maytansine 在 叔丁基过氧化氢 、 bis(acetylacetonate)oxovanadium 作用下， 以 癸烷 、 乙醇 为溶剂， 反应 1.0h， 以59%的产率得到N²'-deacetyl-N²'-(3-methylsulfoxy-1-oxopropyl)maytansine
  参考文献：
  名称：

  Metabolites of Antibody–Maytansinoid Conjugates: Characteristics andin VitroPotencies

  摘要：

  Several antibody-maytansinoid conjugates (AMCs) are in clinical trials for the treatment of various cancers. Each of these conjugates can be metabolized by tumor cells to give cytotoxic maytansinoid metabolites that can kill targeted cells. In preclinical studies in mice, the cytotoxic metabolites initially formed in vivo are further processed in the mouse liver to give several oxidized metabolic species. In this work, the primary AMC metabolites were synthesized and incubated with human liver microsomes (HLMs) to determine if human liver would likely give the same metabolites as those formed in mouse liver. The results of these HLM metabolism studies as well as the subsequent syntheses of the resulting HLM oxidation products are presented. Syntheses of the minor impurities formed during the conjugation of AMCs were also conducted to determine their cytotoxicities and to establish how these impurities would be metabolized by HLM.

  DOI：

  10.1021/mp5007757
• 作为产物：
  描述：

  美登素 、 碘甲烷 在 N,N-二异丙基乙胺 作用下， 以 异丁酰胺 为溶剂， 反应 3.0h， 以65%的产率得到N²'-deacetyl-N²'-(3-methylthio-1-oxopropyl)maytansine
  参考文献：
  名称：

  Elimination of heterogeneous or mixed cell population in tumors

  摘要：

  描述了一种杀灭或抑制由异质或混合细胞群组成的肿瘤的方法。通过选择性地靶向怀疑在特定细胞群体上表达的独特配体，实现了对肿瘤的杀灭或抑制，以及对缺乏该独特配体的细胞群体的杀灭。这些结合物具有治疗用途，因为它们被传递到特定的细胞群体以杀灭这些细胞，并释放细胞毒性药物以杀灭非靶向细胞，从而消除肿瘤。

  公开号：

  US20060233814A1

文献信息

• BIOACTIVE CONJUGATE, PREPARATION METHOD THEREFOR AND USE THEREOF
  申请人：SICHUAN KELUN-BIOTECH BIOPHARMACEUTICAL CO., LTD.

  公开号：US20200347075A1

  公开（公告）日：2020-11-05

  The disclosure relates to a bioactive molecule conjugate, preparation methods and use thereof, particularly relates to a novel bioactive molecule conjugate obtained by improving coupling of the drug and the targeting moiety in an ADC or SMDC, as well as its preparation method and use in the manufacture of a medicament for the treatment of a disease associated with an abnormal cell activity.

  该披露涉及一种生物活性分子结合物，其制备方法及用途，特别涉及通过改善药物与靶向基团在ADC或SMDC中的偶联而获得的一种新型生物活性分子结合物，以及其制备方法和用于制造用于治疗与异常细胞活性相关的疾病的药物。
• [EN] CONJUGATES COMPRISING CELL-BINDING AGENTS AND CYTOTOXIC AGENTS<br/>[FR] CONJUGUÉS COMPRENANT DES AGENTS DE LIAISON CELLULAIRE ET DES AGENTS CYTOTOXIQUES
  申请人：IMMUNOGEN INC

  公开号：WO2016036794A1

  公开（公告）日：2016-03-10

  The invention relates to novel cell-binding agent-cytotoxic agent conjugates, wherein the cell-binding agent (CBA) is covalently linked to the cytotoxic agent through an aldehyde group obtained from oxidation of a 2-hydroxyethylamine moiety on the CBA. The invention also provides methods of preparing the conjugates of the present invention. The invention further provides composition and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the conjugates of the invention.

  该发明涉及一种新型细胞结合剂-细胞毒剂偶联物，其中细胞结合剂（CBA）通过氧化CBA上的2-羟乙胺基团得到的醛基与细胞毒剂共价连接。该发明还提供了制备本发明偶联物的方法。该发明还提供了使用该发明的偶联物抑制异常细胞生长或治疗哺乳动物增生性疾病的组合物和方法。
• ANTI-MET ANTIBODIES, BISPECIFIC ANTIGEN BINDING MOLECULES THAT BIND MET, AND METHODS OF USE THEREOF
  申请人：Regeneron Pharmaceuticals, Inc.

  公开号：US20180134794A1

  公开（公告）日：2018-05-17

  Provided herein are antibodies and bispecific antigen-binding molecules that bind MET and methods of use thereof. The bispecific antigen-binding molecules comprise a first and a second antigen-binding domain, wherein the first and second antigen-binding domains bind to two different (preferably non-overlapping) epitopes of the extracellular domain of human MET. The bispecific antigen-binding molecules are capable of blocking the interaction between human MET and its ligand HGF. The bispecific antigen-binding molecules can exhibit minimal or no MET agonist activity, e.g., as compared to monovalent antigen-binding molecules that comprise only one of the antigen-binding domains of the bispecific molecule, which tend to exert unwanted MET agonist activity. Also included are antibody-drug conjugates (ADCs) comprising the antibodies or bispecific antigen-binding molecules provided herein linked to a cytotoxic agent, radionuclide, or other moiety, as well as methods of treating cancer in a subject by administering to the subject a bispecific antigen-binding molecule or an ADC thereof.

  本文提供了结合MET的抗体和双特异性抗原结合分子，以及它们的使用方法。双特异性抗原结合分子包括第一和第二抗原结合结构域，其中第一和第二抗原结合结构域结合到人类MET的细胞外结构域的两个不同（最好是不重叠的）表位。双特异性抗原结合分子能够阻断人类MET与其配体HGF之间的相互作用。双特异性抗原结合分子可以表现出最小或没有MET激动剂活性，例如，与仅包含双特异性分子的抗原结合结构域之一的单价抗原结合分子相比，后者往往会产生不需要的MET激动剂活性。还包括将本文提供的抗体或双特异性抗原结合分子连接到细胞毒性药物、放射性核素或其他部分的抗体药物共轭物（ADCs），以及通过向受试者施用双特异性抗原结合分子或其ADC来治疗受试者的癌症的方法。
• ANTI-HER2 ANTIBODIES AND IMMUNOCONJUGATES
  申请人：Genentech, Inc.

  公开号：US20160096893A1

  公开（公告）日：2016-04-07

  The invention provides anti-HER2 antibodies and immunoconjugates and methods of using the same.

  这项发明提供了抗HER2抗体和免疫偶联物，以及使用它们的方法。
• [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。