2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazatricosan-23-oic acid | 1375089-61-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazatricosan-23-oic acid
• 英文别名: 2,2-Dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazatricosan-23-oic acid；6-[2-[2-[2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]ethoxy]ethoxy]ethylamino]-6-oxohexanoic acid
• CAS: 1375089-61-4
• 化学式: C₁₉H₃₆N₂O₈
• 分子量: 420.503
• InChiKey: OUHCVHBGISPLOT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  29
• 可旋转键数：
  19
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  132
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazatricosan-23-oic acid 在 盐酸 、 碳酸氢钠 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 3.0h， 生成 [(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-[[6-[2-[2-[2-[2-(2,5-dioxopyrrol-1-yl)ethoxy]ethoxy]ethoxy]ethylamino]-6-oxohexanoyl]-methylamino]propanoate
  参考文献：
  名称：

  Site-Specific Trastuzumab Maytansinoid Antibody–Drug Conjugates with Improved Therapeutic Activity through Linker and Antibody Engineering

  摘要：

  Antibody-drug conjugates. (ADCs) have a significant impact toward the treatment of cancer, as evidenced by the clinical activity of the recently approved ADCs, brentuximab vedotin for Hodgkin lymphoma and ado-trastuzumab emtansine (trastuzumab-MCC-DM1) for metastaic HER2+ breast cancer DM1 is an analog of the natural product maytansine, a microtubule inhibitor that by itself has limited clinical activity and high systemic toxicity. However, by conjugation of DM1 to trastuzumab. the safety was improved and clinical activity was demonstrated. Here, we report that through chemical modification of the linker-drug and antibody engineering, the therapeutic activity of trastuzumab maytansinoid ADCs. can be further improved. These improvements include eliminating DM1 release in the plasma and increasing the drug load by engineering four cysteine residues into the antibody. The chemical synthesis of highly stable linker-drugs and the modification of cysteine residues of engineered site-specific antibodies resulted in a homogeneous ADC with increased therapeutic activity compared to the clinically approved ADC, trastuzumab-MCC-DM1.

  DOI：

  10.1021/jm500552c
• 作为产物：
  描述：

  己二酸 、 tert-butyl N-(2-(2-(2-(2-(((tert-butoxy)carbonyl)amino)ethoxy)ethoxy)ethoxy)ethyl)carbamate 在 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以73%的产率得到2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazatricosan-23-oic acid
  参考文献：
  名称：

  Site-Specific Trastuzumab Maytansinoid Antibody–Drug Conjugates with Improved Therapeutic Activity through Linker and Antibody Engineering

  摘要：

  Antibody-drug conjugates. (ADCs) have a significant impact toward the treatment of cancer, as evidenced by the clinical activity of the recently approved ADCs, brentuximab vedotin for Hodgkin lymphoma and ado-trastuzumab emtansine (trastuzumab-MCC-DM1) for metastaic HER2+ breast cancer DM1 is an analog of the natural product maytansine, a microtubule inhibitor that by itself has limited clinical activity and high systemic toxicity. However, by conjugation of DM1 to trastuzumab. the safety was improved and clinical activity was demonstrated. Here, we report that through chemical modification of the linker-drug and antibody engineering, the therapeutic activity of trastuzumab maytansinoid ADCs. can be further improved. These improvements include eliminating DM1 release in the plasma and increasing the drug load by engineering four cysteine residues into the antibody. The chemical synthesis of highly stable linker-drugs and the modification of cysteine residues of engineered site-specific antibodies resulted in a homogeneous ADC with increased therapeutic activity compared to the clinically approved ADC, trastuzumab-MCC-DM1.

  DOI：

  10.1021/jm500552c

文献信息

• ALANINYL MAYTANSINOL ANTIBODY CONJUGATES
  申请人：Flygare John A.

  公开号：US20120121615A1

  公开（公告）日：2012-05-17

  Linker-drug intermediates of Formula I are conjugated to antibodies to form antibody-drug conjugates where the drug moiety is an N-methylalaninyl-maytansinoid. L is E is n is 2, 3, 4, 5, or 6; m is 2, 3 or 4; and q is 0 or 1.

  Formula I的连接药物中间体被结合到抗体上，形成抗体药物结合物，其中药物部分是N-甲基丙氨酰马坦西诺因。L是E，n是2、3、4、5或6；m是2、3或4；q是0或1。
• [EN] ALANINYL MAYTANSINOL ANTIBODY CONJUGATES<br/>[FR] CONJUGUÉS D'ANTICORPS ALANINYL-MAYTANSINOL
  申请人：GENENTECH INC

  公开号：WO2012074757A1

  公开（公告）日：2012-06-07

  Linker-drug intermediates of Formula I are conjugated to antibodies to form antibody-drug conjugates where the drug moiety is an N-methylalaninyl-maytansinoid. L is Formula IA; E is Formula IB or Formula IC; n is 2, 3, 4, 5, or 6; m is 2, 3 or 4; and q is 0 or 1.