4-formyl-N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[(4-formylbenzoyl)amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]benzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-formyl-N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[(4-formylbenzoyl)amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]benzamide
• 化学式: C₅₆H₉₂N₂O₂₃
• 分子量: 1161.35
• InChiKey: AAQIAANAQHHZDV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.7
• 重原子数：
  81
• 可旋转键数：
  64
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  268
• 氢给体数：
  2
• 氢受体数：
  23

反应信息

• 作为产物：
  描述：

  O,O'-bis(2-aminoethyl)octadecaethylene glycol 、 对醛基苯甲酸 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以75%的产率得到4-formyl-N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[(4-formylbenzoyl)amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]benzamide
  参考文献：
  名称：

  A Chemically Cross-Linked Knottin Dimer Binds Integrins with Picomolar Affinity and Inhibits Tumor Cell Migration and Proliferation

  摘要：

  Molecules that target and inhibit alpha(v)beta(3), alpha(v)beta(5), and alpha(5)beta(1) integrins have generated great interest because of the role of these receptors in mediating angiogenesis and metastasis. Attempts to increase the binding affinity and hence the efficacy of integrin inhibitors by dimerization have been marginally effective. In the present work, we achieved this goal by using oxime-based chemical conjugation to synthesize dimers of integrin-binding cystine knot (knottin) miniproteins with low-picomolar binding affinity to tumor cells. A non-natural amino acid containing an aminooxy side chain was introduced at different locations within a knottin monomer and reacted with dialdehyde-containing cross-linkers of different lengths to create knottin dimers with varying molecular topologies. Dimers cross-linked through an aminooxy functional group located near the middle of the protein exhibited higher apparent binding affinity to integrin-expressing tumor cells compared with dimers cross-linked through an aminooxy group near the C-terminus. In contrast, the cross-linker length had no effect on the integrin binding affinity. A chemical-based dimerization strategy was critical, as knottin dimers created through genetic fusion to a bivalent antibody domain exhibited only modest improvement (less than 5-fold) in tumor cell binding relative to the knottin monomer. The best oxime-conjugated knottin dimer achieved an unprecedented 150-fold increase in apparent binding affinity over the knottin monomer. Also, this dimer bound 3650-fold stronger and inhibited tumor cell migration and proliferation compared with cilengitide, an integrin-targeting peptidomimetic that performed poorly in recent clinical trials, suggesting promise for further therapeutic development.

  DOI：

  10.1021/ja508416e

文献信息

• Conjugated knottin mini-proteins containing non-natural amino acids
  申请人：The Board of Trustees of the Leland Stanford Junior University

  公开号：US10407477B2

  公开（公告）日：2019-09-10

  Disclosed are knottin peptides containing non-natural amino acids so that they can be formed by chemical conjugation into two or more knottin monomers. The knottin monomers comprise a non-natural amino acid such as an aminooxy residue within the polypeptide sequence. The exemplified dimers were produced by oxime formation between two aldehyde groups present on a polyether linker and an aminooxy functional group that was site-specifically incorporated the knottin. Knottins variants based on EETI (Ecballium elaterium trypsin inhibitor) and AgRP (Agouti-related protein) were engineered to contain integrin-binding loops. These dimers were shown to have increased binding strength to integrins on U87MG tumor cells, achieving significant increases in inhibition of cell adhesion and proliferation. Also disclosed are knottin monomers comprising an aminooxy residue; these may be conjugated to molecules such as doxorubicin.

  本发明公开了含有非天然氨基酸的节蛋白肽，通过化学共轭可以形成两个或多个节蛋白单体。结素单体包含非天然氨基酸，如多肽序列中的氨基氧基残基。示例的二聚体是通过聚醚连接体上的两个醛基团与特定位点掺入 knottin 的氨基氧基官能团之间的肟化作用产生的。以 EETI（Ecballium elaterium trypsin inhibitor）和 AgRP（Agouti-related protein）为基础的 Knottins 变体被设计成含有整合素结合环。结果表明，这些二聚体与 U87MG 肿瘤细胞上的整合素的结合强度增加，对细胞粘附和增殖的抑制作用显著增强。还公开了含有氨基氧基残基的结素单体；这些单体可与多柔比星等分子共轭。
• CONJUGATED KNOTTIN MINI-PROTEINS CONTAINING NON-NATURAL AMINO ACIDS
  申请人：THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY

  公开号：US20150266936A1

  公开（公告）日：2015-09-24

  Disclosed are knottin peptides containing non-natural amino acids so that they can be formed by chemical conjugation into two or more knottin monomers. The knottin monomers comprise a non-natural amino acid such as an aminooxy residue within the polypeptide sequence. The exemplified dimers were produced by oxime formation between two aldehyde groups present on a polyether linker and an aminooxy functional group that was site-specifically incorporated the knottin. Knottins variants based on EETI ( Ecballium elaterium trypsin inhibitor) and AgRP (Agouti-related protein) were engineered to contain integrin-binding loops. These dimers were shown to have increased binding strength to integrins on U87MG tumor cells, achieving significant increases in inhibition of cell adhesion and proliferation. Also disclosed are knottin monomers comprising an aminooxy residue; these may be conjugated to molecules such as doxorubicin.
• US9587001B2
  申请人：——

  公开号：US9587001B2

  公开（公告）日：2017-03-07
• [EN] CONJUGATED KNOTTIN MINI-PROTEINS CONTAINING NON-NATURAL AMINO ACIDS<br/>[FR] MINIPROTÉINES KNOTTINES CONJUGUÉES CONTENANT DES ACIDES AMINÉS NON NATURELS
  申请人：UNIV LELAND STANFORD JUNIOR

  公开号：WO2014063012A1

  公开（公告）日：2014-04-24

  Disclosed are knottin peptides containing non-natural amino acids so that they can be formed by chemical conjugation into two or more knottin monomers. The knottin monomers comprise a non-natural amino acid such as an aminooxy residue within the polypeptide sequence. The exemplified dimers were produced by oxime formation between two aldehyde groups present on a polyether linker and an aminooxy functional group that was site-specifically incorporated the knottin. Knottins variants based on EETI (Ecballium elaterium trypsin inhibitor) and AgRP (Agouti-related protein) were engineered to contain integrin- binding loops. These dimers were shown to have increased binding strength to integrins on U87MG tumor cells, achieving significant increases in inhibition of cell adhesion and proliferation. Also disclosed are knottin monomers comprising an aminooxy residue; these may be conjugated to molecules such as doxorubicin.