N²'-deacetyl-N²'-(4-methyl-4-methythio-1-oxopentyl)maytansine | 890654-03-2

• 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'-(4-methyl-4-methythio-1-oxopentyl)maytansine
• 英文别名: N2'-deacetyl-N2'-(4-methylthio-4-methyl-1-oxopentyl)-maytansine；N2'-Deacetyl-N2'-(4-methyl-4-methylthio-1-oxopentyl)maytansine；[(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-(4-methyl-4-methylsulfanylpentanoyl)amino]propanoate
• CAS: 890654-03-2
• 化学式: C₃₉H₅₆ClN₃O₁₀S
• 分子量: 794.407
• InChiKey: AYWIIXDQRUFQGH-SIDGEOBYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  54
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  182
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  N²'-deacetyl-N²'-(4-methyl-4-methythio-1-oxopentyl)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65%的产率得到N²'-deacetyl-N²'-(4-methyl-4-methylsulfoxy-1-oxopentyl)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：

  DM4 、 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57%的产率得到N²'-deacetyl-N²'-(4-methyl-4-methythio-1-oxopentyl)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

• [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。
• [EN] ANTI-CCR7 ANTIBODY DRUG CONJUGATES<br/>[FR] CONJUGUÉS ANTICORPS-MÉDICAMENT ANTI-CCR7
  申请人：NOVARTIS AG

  公开号：WO2018142322A1

  公开（公告）日：2018-08-09

  This application discloses anti-CCR7 antibodies, antigen binding fragments thereof, and antibody drug conjugates of said antibodies or antigen binding fragments. The invention also relates to methods of treating or preventing cancer using the antibodies, antigen binding fragments, and antibody drug conjugates. Also disclosed herein are methods of making the antibodies, antigen binding fragments, and antibody drug conjugates, and methods of using the antibodies and antigen binding fragments as diagnostic reagents.

  本申请公开了抗CCR7抗体、其抗原结合片段，以及所述抗体或抗原结合片段的抗体药物结合物。该发明还涉及使用这些抗体、抗原结合片段和抗体药物结合物治疗或预防癌症的方法。本文还公开了制备这些抗体、抗原结合片段和抗体药物结合物的方法，以及将这些抗体和抗原结合片段用作诊断试剂的方法。
• Highly Selective Directed Iridium‐Catalyzed Hydrogen Isotope Exchange Reactions of Aliphatic Amides
  作者：Mégane Valero、Remo Weck、Stefan Güssregen、Jens Atzrodt、Volker Derdau

  DOI：10.1002/anie.201804010

  日期：2018.7.2

  For the first time, we describe highly selective homogeneous iridium‐catalyzed hydrogen isotope exchange (HIE) of unactivated C(sp3) centers in aliphatic amides. When using the commercially available Kerr catalyst, the HIE with a series of common antibody–drug conjugate (ADC) linker side chains proceeds with high yields, high regioselectivity, and with deuterium incorporation up to 99 %. The method

  首次，我们描述了未活化的C（sp 3）的高选择性均相铱催化的氢同位素交换（HIE））以脂肪族酰胺为中心。当使用市售的Kerr催化剂时，带有一系列常见抗体-药物偶联物（ADC）接头侧链的HIE的收率高，区域选择性高，并且氘的掺入率高达99％。该方法可完全转化为of化学的特定要求，并且通过直接may标记美登木素生物碱来证明其有效性。该方法的范围可以扩展到简单氨基酸，对甘氨酸和丙氨酸具有很高的HIE活性。在二肽和三肽中，观察到非常有趣的依赖保护基团的可调选择性。DFT计算使人们深入了解了过渡态的能量，从而解释了观察到的选择性和氨基酸保护基团的影响。
• [EN] CONJUGATES OF CYSTEINE ENGINEERED ANTIBODIES<br/>[FR] CONJUGUÉS D'ANTICORPS À CYSTÉINE MODIFIÉE
  申请人：IMMUNOGEN INC

  公开号：WO2017004025A1

  公开（公告）日：2017-01-05

  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 engineered Cys, such as an engineered Cys in the heavy chain CH3 domain, at a position corresponds to the EU/OU numbering position 442 (or C442) on an antibody 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.

  本发明涉及一种新型细胞结合剂-细胞毒剂偶联物，其中所述细胞结合剂（CBA）通过工程半胱氨酸与细胞毒剂共价结合，例如在重链CH3域中的工程半胱氨酸，其位置对应于抗体CBA上的EU/OU编号位置442（或C442）。本发明还提供了制备本发明偶联物的方法。本发明还提供了使用该偶联物的组合物和方法，用于抑制异常细胞生长或治疗哺乳动物中的增生性疾病。
• CYSTEINE ENGINEERED ANTIBODIES AND CONJUGATES
  申请人：Genentech, Inc.

  公开号：US20140288280A1

  公开（公告）日：2014-09-25

  Cysteine engineered antibodies comprising a free cysteine amino acid in the heavy chain or light chain are prepared by mutagenizing a nucleic acid sequence of a parent antibody and replacing one or more amino acid residues by cysteine to encode the cysteine engineered antibody; expressing the cysteine engineered antibody; and isolating the cysteine engineered antibody. Certain highly reactive cysteine engineered antibodies were identified by the PHESELECTOR assay. Isolated cysteine engineered antibodies may be covalently attached to a capture label, a detection label, a drug moiety, or a solid support.

  利用突变技术将母体抗体的核酸序列进行突变，替换一个或多个氨基酸残基，以编码含有重链或轻链中的一个自由半胱氨酸的半胱氨酸工程抗体；表达半胱氨酸工程抗体；并分离半胱氨酸工程抗体。PHESELECTOR测定鉴定了某些高反应性的半胱氨酸工程抗体。分离的半胱氨酸工程抗体可以共价地附着在捕获标签、检测标签、药物部分或固体支持体上。