17-(4-aminobutyloamino)-17-demethoxy geldanamycin

• 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: 17-(4-aminobutyloamino)-17-demethoxy geldanamycin
• 英文别名: [(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-(4-aminobutylamino)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate
• 化学式: C₃₂H₄₈N₄O₈
• 分子量: 616.755
• InChiKey: PYFSBTHEFUQNEG-LMZWQJSESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  44
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  192
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  异烟酸 、 17-(4-aminobutyloamino)-17-demethoxy geldanamycin 在 N-羟基丁二酰亚胺 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 17-(4-(isonicotinamido)butylamino)-17-demethoxygeldanamycin
  参考文献：
  名称：

  Discovery of Novel 17-Phenylethylaminegeldanamycin Derivatives as Potent Hsp90 Inhibitors

  摘要：

  Twenty‐six 17‐phenylethylamine‐modified geldanamycin derivatives were synthesized and evaluated for antiproliferation activity in human cancer cell lines, LNCaP and MDA‐MB‐231. Five derivatives (2j, 2q, 2v, 2x, and 2y) showed excellent in vitro antitumor activities. Among them, compound 2y was the most potent lead, with IC50 values of 0.27 ± 0.11 and 0.86 ± 0.23 μm for LNCaP and MDA‐MB‐231, respectively. In particular, compound 2y was more active than its precursor geldanamycin against LNCap cells. Liver injury test in mice demonstrated that 2y group showed no significant difference for serum alanine aminotransferase (ALT) activity versus vehicle control, indicating that 2y was a promising antitumor candidate. Preliminary structure–activity relationship (SAR) and molecular dynamics (MD) simulations of this new series of geldanamycin derivatives were also investigated, suggesting a theoretical model of 17‐phenylethylaminegeldanamycins binding to Hsp90.

  DOI：

  10.1111/cbdd.12371
• 作为产物：
  描述：

  四亚甲基二胺 、 格尔德霉素 以 氯仿 为溶剂， 以84%的产率得到17-(4-aminobutyloamino)-17-demethoxy geldanamycin
  参考文献：
  名称：

  Synthesis and evaluation of antiproliferative activity of a geldanamycin–Herceptin™ immunoconjugate

  摘要：

  Geldanamycin was modified with 1,4-diaminobutane to introduce a primary amine that was subsequently employed to provide a maleimide for protein linkage. Monoclonal antibody Herceptin(TM) was then derivatized to generate thiol groups that reacted with the maleimide derivative to produce the immunoconjugate. The product showed antiproliferative activity greater than native Herceptin(TM). (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(00)00155-4

文献信息

• Engineered polypeptide conjugates using transglutaminase
  申请人：RINAT NEUROSCIENCE CORP.

  公开号：US10195289B2

  公开（公告）日：2019-02-05

  The present invention provides engineered polypeptide conjugates (e.g., antibody-drug-conjugates) comprising specific acyl donor glutamine-containing tags and amine donor agents. The invention also provides methods of making such engineered polypeptide conjugates using transglutaminase and methods of using thereof.

  本发明提供了包含特定酰基供体谷氨酰胺标签和胺供体制剂的工程多肽结合物（如抗体-药物-结合物）。本发明还提供了使用转谷氨酰胺酶制造这种工程多肽共轭物的方法及其使用方法。
• Engineered polypeptide conjugates and methods for making thereof using transglutaminase
  申请人：PFIZER INC.

  公开号：US10941216B2

  公开（公告）日：2021-03-09

  The present invention provides engineered polypeptide conjugates (e.g., antibody-drug-conjugates, toxin-(biocompatible polymer) conjugates, antibody-(biocompatible polymer) conjugates, and bispecific antibodies) comprising acyl donor glutamine-containing tags and amine donor agents. In one aspect, the invention provides an engineered Fc-containing polypeptide conjugate comprising the formula (Fc-containing polypeptide)-T-A, wherein T is an acyl donor glutamine-containing tag engineered at a specific site or comprises an endogenous glutamine made reactive by the Fc-containing polypeptide engineering, wherein A is an amine donor agent, and wherein the amine donor agent is site-specifically conjugated to the acyl donor glutamine-containing tag or the endogenous glutamine. The invention also provides methods of making engineered polypeptide conjugates using transglutaminase.

  本发明提供了包含酰基供体谷氨酰胺标签和胺供体制剂的工程化多肽共轭物（例如，抗体-药物-共轭物、毒素-（生物相容性聚合物）共轭物、抗体-（生物相容性聚合物）共轭物和双特异性抗体）。在一个方面，本发明提供了一种工程化的含 Fc 多肽共轭物，其包含式（含 Fc 多肽）-T-A，其中 T 是在特定位点工程化的含酰基供体谷氨酰胺标签，或包含通过含 Fc 多肽工程化使之反应的内源性谷氨酰胺、其中 A 是胺供体剂，胺供体剂与含酰基供体谷氨酰胺标签或内源性谷氨酰胺特异性地连接。本发明还提供了使用转谷氨酰胺酶制造工程多肽共轭物的方法。
• Synthesis of a red-shifted fluorescence polarization probe for Hsp90
  作者：Kamalika Moulick、Cristina C. Clement、Julia Aguirre、Joungnam Kim、Yanlong Kang、Sara Felts、Gabriela Chiosis

  DOI：10.1016/j.bmcl.2006.06.025

  日期：2006.9

  The synthesis of a red-shifted cy3B-GM ligand and its evaluation as a fluorescence polarization probe for Hsp90 is presented. (c) 2006 Elsevier Ltd. All rights reserved.
• ENGINEERED POLYPEPTIDE CONJUGATES AND METHODS FOR MAKING THEREOF USING TRANSGLUTAMINASE
  申请人：Pons Jaume

  公开号：US20130230543A1

  公开（公告）日：2013-09-05

  The present invention provides engineered polypeptide conjugates (e.g., antibody-drug-conjugates, toxin-(biocompatible polymer) conjugates, antibody-(biocompatible polymer) conjugates, and bispecific antibodies) comprising acyl donor glutamine-containing tags and amine donor agents. In one aspect, the invention provides an engineered Fc-containing polypeptide conjugate comprising the formula (Fc-containing polypeptide)-T-A, wherein T is an acyl donor glutamine-containing tag engineered at a specific site or comprises an endogenous glutamine made reactive by the Fc-containing polypeptide engineering, wherein A is an amine donor agent, and wherein the amine donor agent is site-specifically conjugated to the acyl donor glutamine-containing tag or the endogenous glutamine. The invention also provides methods of making engineered polypeptide conjugates using transglutaminase.
• ANTIBODY-DRUG CONJUGATES WITH HIGH DRUG LOADING
  申请人：Rinat Neuroscience Corp.

  公开号：US20170043033A1

  公开（公告）日：2017-02-16

  The present invention provides transglutaminase-mediated antibody-drug conjugates with high anti-body-drug ratio (DAR) comprising 1) glutamine-containing tags, endogenous glutamines, and/or endogenous glutamines made reactive by antibody engineering or an engineered transglutaminase (e.g., with altered substrate specifity); and 2) amine donor agents comprising amine donor units, linkers, and agent moieties, wherein the DAR is at least about 5. The invention also provides methods of making and methods of using such higher drug loaded antibody-drug conjugates.