O-(2-azidoethyl)-O'-[(N-diglycolyl-2-aminoethyl)-Phe-Lys(MMT)-PAB-OCO-20-O-SN-38-10-O-tert-butoxycarbonyl]heptaethyleneglycol | 1036847-91-2

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 喜树碱
• 英文名称: O-(2-azidoethyl)-O'-[(N-diglycolyl-2-aminoethyl)-Phe-Lys(MMT)-PAB-OCO-20-O-SN-38-10-O-tert-butoxycarbonyl]heptaethyleneglycol
• 英文别名: N3-PEG-Phe-Lys(MMT)-PABOCO-20-O-SN38-10-O-BOC；[(19S)-19-[[4-[[(2S)-2-[[(2S)-2-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxoethoxy]acetyl]amino]-3-phenylpropanoyl]amino]-6-[[(4-methoxyphenyl)-diphenylmethyl]amino]hexanoyl]amino]phenyl]methoxycarbonyloxy]-10,19-diethyl-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-7-yl] tert-butyl carbonate
• CAS: 1036847-91-2
• 化学式: C₉₂H₁₁₂N₁₀O₂₃
• 分子量: 1725.95
• InChiKey: XPDJMLNQCYKXQT-LMNIUURLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.5
• 重原子数：
  125
• 可旋转键数：
  59
• 环数：
  10.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  366
• 氢给体数：
  5
• 氢受体数：
  27

反应信息

• 作为反应物：
  描述：

  O-(2-azidoethyl)-O'-[(N-diglycolyl-2-aminoethyl)-Phe-Lys(MMT)-PAB-OCO-20-O-SN-38-10-O-tert-butoxycarbonyl]heptaethyleneglycol 、 4-((2,5-二氧代-2,5-二氢-1H-吡咯-1-基)甲基)-N-(丙-2-炔-1-基)环己烷甲 在 copper(I) bromide 作用下， 以 水 、 二甲基亚砜 为溶剂， 反应 0.5h， 以79%的产率得到O-{2-[(1,2,3-triazolyl)-4-[4-(N-maleimidomethyl)cyclohexane-1-carboxamidomethyl]]ethyl}-O'-[(N-diglycolyl-2-aminoethyl)-Phe-Lys(MMT)-PAB-OCO-20-O-SN-38-10-O-tert-butoxycarbonyl]heptaethyleneglycol
  参考文献：
  名称：

  Antibody Conjugates of 7-Ethyl-10-hydroxycamptothecin (SN-38) for Targeted Cancer Chemotherapy

  摘要：

  CPT-11 is a clinically used cancer drug, and it is a prodrug of the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin). To bypass the need for the in vivo conversion of CPT-11 and increase the therapeutic index, bifunctional derivatives of SN-38 were prepared for use in anti body-based targeted therapy of cancer. The general synthetic scheme incorporated an acetylene-azide click cycloaddition step in the design, a short polyethylene glycol spacer for aqueous solubility, and a maleimide group conjugation. Conjugates of a humanized anti-CEACAM5 monoclonal antibody, hMN-14, prepared using, these SN-38 derivatives were evaluated in vitro for stability in buffer and human serum and for antigen-binding and cytotoxicity in a human colon adenocarcinoma cell line. Conjugates of hMN-14 and SN-38 derivatives 16 and 17 were found promising for further development.

  DOI：

  10.1021/jm800719t
• 作为产物：
  描述：

  tert-butyl [(19S)-19-chlorocarbonyloxy-10,19-diethyl-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-7-yl]carbonate 、 O-(2-azidoethyl)-O'-[(N-diglycolyl-2-aminoethyl)-Phe-Lys(MMT)-PAB-OH]heptaethyleneglycol 以60%的产率得到O-(2-azidoethyl)-O'-[(N-diglycolyl-2-aminoethyl)-Phe-Lys(MMT)-PAB-OCO-20-O-SN-38-10-O-tert-butoxycarbonyl]heptaethyleneglycol
  参考文献：
  名称：

  Polymeric Carriers of Therapeutic Agents and Recognition Moieties for Antibody-Based Targeting of Disease Sites

  摘要：

  本发明涉及将治疗剂递送到目标细胞、组织或生物体的方法和组合物。在优选的实施例中，治疗剂以负载治疗剂的聚合物形式递送，该聚合物可能包含一个或多个治疗剂的许多拷贝。在更优选的实施例中，聚合物可以与含有一种或多种半抗原的肽部分结合，例如HSG。例如，通过使用双特异性或多特异性抗体或片段的预定位技术，将治疗剂-聚合物-肽复合物递送到目标细胞，该抗体或片段至少有一个结合臂识别半抗原，并且至少有第二个结合臂特异性地结合到与疾病或病原体相关的抗原，例如肿瘤相关抗原。本发明提供了合成和使用此类负载治疗剂的聚合物及其缀合物的方法。

  公开号：

  US20080171067A1

文献信息

• Polymeric Carriers of Therapeutic Agents and Recognition Moieties for Antibody-Based Targeting of Disease Sites
  申请人：Govindan Serengulam V.

  公开号：US20080171067A1

  公开（公告）日：2008-07-17

  The present invention concerns methods and compositions for delivery of therapeutic agents to target cells, tissues or organisms. In preferred embodiments, the therapeutic agents are delivered in the form of therapeutic-loaded polymers that may comprise many copies of one or more therapeutic agents. In more preferred embodiments, the polymer may be conjugated to a peptide moiety that contains one or more haptens, such as HSG. The agent-polymer-peptide complex may be delivered to target cells by, for example, a pre-targeting technique utilizing bispecific or multispecific antibodies or fragments, having at least one binding arm that recognizes the hapten and at least a second binding arm that binds specifically to a disease or pathogen associated antigen, such as a tumor associated antigen. Methods for synthesizing and using such therapeutic-loaded polymers and their conjugates are provided.

  本发明涉及将治疗剂递送到目标细胞、组织或生物体的方法和组合物。在优选的实施例中，治疗剂以负载治疗剂的聚合物形式递送，该聚合物可能包含一个或多个治疗剂的许多拷贝。在更优选的实施例中，聚合物可以与含有一种或多种半抗原的肽部分结合，例如HSG。例如，通过使用双特异性或多特异性抗体或片段的预定位技术，将治疗剂-聚合物-肽复合物递送到目标细胞，该抗体或片段至少有一个结合臂识别半抗原，并且至少有第二个结合臂特异性地结合到与疾病或病原体相关的抗原，例如肿瘤相关抗原。本发明提供了合成和使用此类负载治疗剂的聚合物及其缀合物的方法。
• Antibody Conjugates of 7-Ethyl-10-hydroxycamptothecin (SN-38) for Targeted Cancer Chemotherapy
  作者：Sung-Ju Moon、Serengulam V. Govindan、Thomas M. Cardillo、Christopher A. D’Souza、Hans J. Hansen、David M. Goldenberg

  DOI：10.1021/jm800719t

  日期：2008.11.13

  CPT-11 is a clinically used cancer drug, and it is a prodrug of the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin). To bypass the need for the in vivo conversion of CPT-11 and increase the therapeutic index, bifunctional derivatives of SN-38 were prepared for use in anti body-based targeted therapy of cancer. The general synthetic scheme incorporated an acetylene-azide click cycloaddition step in the design, a short polyethylene glycol spacer for aqueous solubility, and a maleimide group conjugation. Conjugates of a humanized anti-CEACAM5 monoclonal antibody, hMN-14, prepared using, these SN-38 derivatives were evaluated in vitro for stability in buffer and human serum and for antigen-binding and cytotoxicity in a human colon adenocarcinoma cell line. Conjugates of hMN-14 and SN-38 derivatives 16 and 17 were found promising for further development.