Methyl 4-(cyclooct-2-yn-1-yloxymethyl)benzoate | 1131041-36-5

• 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: Methyl 4-(cyclooct-2-yn-1-yloxymethyl)benzoate
• CAS: 1131041-36-5
• 化学式: C₁₇H₂₀O₃
• 分子量: 272.344
• InChiKey: CKYPJWJOWPDJPB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.33
• 重原子数：
  20.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  35.53
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  Methyl 4-(cyclooct-2-yn-1-yloxymethyl)benzoate 在 水 、 lithium hydroxide 作用下， 以 甲醇 为溶剂， 以89%的产率得到4-[(cyclooct-2-yn-1-yloxy)methyl]benzoic acid
  参考文献：
  名称：

  Application of Strain-Promoted Azide–Alkyne Cycloaddition and Tetrazine Ligation to Targeted Fc-Drug Conjugates

  摘要：

  We have previously described an approach whereby antibody Fc fragments harboring a single C-terminal selenocysteine residue (Fc-Sec) are directed against a variety of targets by changing the peptide or small molecule to which they are conjugated. In the present work, we describe methodology for improving the efficacy of these Fc-Sec conjugates by incorporating cytotoxic drugs. The Fc-Sec protein is first programmed to target specific tumor cell types by attachment of a bifunctional linker that contains a "clickable" handle (e.g., cyclobutane or cyclooctyne) in addition to a tumor cell-binding peptide or small molecule. Following Fc-Sec conjugation, a cytotoxic warhead is then attached by cycloaddition reactions of tetrazine or azide-containing linker. To validate this approach, we used a model system in which folic acid (FA) is the targeting moiety and a disulfide-linked biotin moiety serves as a cytotoxic drug surrogate. We demonstrated successful targeting of Fc-Sec proteins to folate-receptor expressing tumor cells. Tetrazine ligation was found to be an efficient method for biotin "arming" of the folate-targeted Fc-Sec proteins. We also report novel bioconjugation methodologies that use [4 + 2] cycloaddition reactions between tetrazines and cyclooctynes.

  DOI：

  10.1021/bc300052u
• 作为产物：
  描述：

  在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 二甲基亚砜 为溶剂， 以71%的产率得到Methyl 4-(cyclooct-2-yn-1-yloxymethyl)benzoate
  参考文献：
  名称：

  Application of Strain-Promoted Azide–Alkyne Cycloaddition and Tetrazine Ligation to Targeted Fc-Drug Conjugates

  摘要：

  We have previously described an approach whereby antibody Fc fragments harboring a single C-terminal selenocysteine residue (Fc-Sec) are directed against a variety of targets by changing the peptide or small molecule to which they are conjugated. In the present work, we describe methodology for improving the efficacy of these Fc-Sec conjugates by incorporating cytotoxic drugs. The Fc-Sec protein is first programmed to target specific tumor cell types by attachment of a bifunctional linker that contains a "clickable" handle (e.g., cyclobutane or cyclooctyne) in addition to a tumor cell-binding peptide or small molecule. Following Fc-Sec conjugation, a cytotoxic warhead is then attached by cycloaddition reactions of tetrazine or azide-containing linker. To validate this approach, we used a model system in which folic acid (FA) is the targeting moiety and a disulfide-linked biotin moiety serves as a cytotoxic drug surrogate. We demonstrated successful targeting of Fc-Sec proteins to folate-receptor expressing tumor cells. Tetrazine ligation was found to be an efficient method for biotin "arming" of the folate-targeted Fc-Sec proteins. We also report novel bioconjugation methodologies that use [4 + 2] cycloaddition reactions between tetrazines and cyclooctynes.

  DOI：

  10.1021/bc300052u

文献信息

• PROCESS FOR THE CYCLOADDITION OF A(HETERO)ARYL 1,3-DIPOLE COMPOUND WITH A (HETERO)CYCLOALKYNE
  申请人：SynAffix B.V.

  公开号：EP3925951A1

  公开（公告）日：2021-12-22

  The present invention relates to a process comprising the step of reacting a (hetero)aryl 1,3-dipole compound with a (hetero)cycloalkyne, wherein: a (hetero)aryl 1,3-dipole compound is defined as a compound comprising a 1,3-dipole functional group, wherein the 1,3-dipole functional group is bonded to a (hetero)aryl group, and wherein the (hetero)aryl 1,3-dipole compound is a (hetero)aryl azide or a (hetero)aryl diazo compound; wherein: (i) the (hetero)aryl group of the (hetero)aryl 1,3-dipole compound comprises one or more substituents having a positive value for the para-Hammett substituent constant σp and/or the meta-Hammett substituent constant σm, and/or (ii) the (hetero)aryl group of the (hetero)aryl 1,3-dipole compound is an electron-poor (hetero)aryl group, wherein an electron-poor (hetero)aryl group is: (ii-a) a (hetero)aryl group wherein the (hetero)aromatic ring system is bearing a positive charge, and/or (ii-b) a (hetero)aryl group wherein the ratio number of π-electrons present in the (hetero)aromatic ring system} : number of protons present in the nuclei of the (hetero)aromatic ring system} is lower than 0.167 for a 6-membered ring, or lower than 0.200 for a 5-membered ring; and wherein the (hetero)cycloalkyne is a (hetero)cyclooctyne or a (hetero)cyclononyne according to Formula (1): The invention also relates to the products obtainable by the process according to the invention.

  本发明涉及一种工艺，包括使(杂)芳基 1,3-二极化合物与(杂)环烷烃反应的步骤，其中： (杂)芳基 1,3-二极化合物定义为包含 1,3-二极官能团的化合物，其中 1,3-二极官能团与(杂)芳基键合，且(杂)芳基 1,3-二极化合物为(杂)芳基叠氮化物或(杂)芳基重氮化合物； 其中 (i) (杂)芳基 1,3-二极化合物的(杂)芳基包括一个或多个对位-哈梅特基常数 σp 和/或元-哈梅特基常数 σm 为正值的取代基，和/或 (ii) (杂)芳基 1,3-二极化合物的(杂)芳基是贫电子的(杂)芳基，其中贫电子的(杂)芳基是： (ii-a) (杂)芳环系统带正电荷的(杂)芳基，和/或 (ii-b) (杂)芳基，其中(杂)芳环系中存在的π电子数}与(杂)芳环系核中存在的质子数}之比，对于 6 元环，低于 0.167，或者对于 5 元环，低于 0.200； 其中(杂)环炔烃是符合式(1)的(杂)环辛炔或(杂)环壬炔： 本发明还涉及根据本发明的工艺可获得的产品。