2-(4-benzyloxy-2-(5-aminobenzofuran-2-carboxamido)phenyl)ethyl chloride | 413577-37-4

• 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: 2-(4-benzyloxy-2-(5-aminobenzofuran-2-carboxamido)phenyl)ethyl chloride
• 英文别名: 5-amino-N-[2-(2-chloroethyl)-5-phenylmethoxyphenyl]-1-benzofuran-2-carboxamide
• CAS: 413577-37-4
• 化学式: C₂₄H₂₁ClN₂O₃
• 分子量: 420.895
• InChiKey: JEGJSAHGESXLAV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  77.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(4-benzyloxy-2-(5-aminobenzofuran-2-carboxamido)phenyl)ethyl chloride 在 palladium on activated charcoal 、 cadmium lead 乙酸铵 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 5-[3-((S)-7-Methoxy-5-oxo-2,3,5,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yloxy)-propionylamino]-benzofuran-2-carboxylic acid [2-(2-chloro-ethyl)-5-hydroxy-phenyl]-amide
  参考文献：
  名称：

  DNA interstrand crosslinking agents: Synthesis, DNA interactions, and cytotoxicity of dimeric achiral seco-amino-CBI and conjugates of achiral seco-amino-CBI with pyrrolobenzodiazepine (PBD)

  摘要：

  The design and synthesis of three novel bisalkylating agents derived from the achiral seco-duocarmycin or CC-1065 analogs and pyrrolobenzodiazepines (PBDs) are described: achiral seco-CBI (cyclopropanebenz[e]indoline)-PBD 11, achiral seco-CI-PBD 12, and achiral seco-CBI dimer 13. Compounds 11 and 12 demonstrated enhanced cytotoxicity over the monomer counterparts against the growth of PS 15 murine mastocytoma cells in culture. Conjugate 11 was found to covalently react with adenine-N3 positions within the minor groove at AT-rich sequences and to produce DNA interstrand crosslinks. Both compounds were found to induce apoptosis in P815 cells. Due to its poor water solubility, dimer 13 did not give any appreciable DNA binding or cytotoxicity. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.08.005
• 作为产物：
  描述：

  2-(4-benzyloxy-2-nitrophenyl)ethyl chloride 在 platinum(IV) oxide benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 49.5h， 生成 2-(4-benzyloxy-2-(5-aminobenzofuran-2-carboxamido)phenyl)ethyl chloride
  参考文献：
  名称：

  通过非手性癸二酮-环丙烷二氢吲哚-2-苯并呋喃甲酰胺和吡咯-咪唑聚酰胺的量身定制的发夹共轭物，对DNA进行序列特异性识别。

  摘要：

  由γ-氨基丁酸酯连接的非手性癸二酸环丙烷二氢-2-苯并呋喃甲酰胺（非手性Seco-CI-Bf）和三种二酰胺（ImPy 1，PyIm 2和PyPy 3，其中Py为吡咯，Im为咪唑）的发夹共轭物组，进行了合成。通过热诱导DNA切割实验确定在小沟中非手性CI部分与腺嘌呤-N3的序列特异性共价烷基化。结果提供了证据，可以根据一组通用规则将非手性seco-CI-Bf-γ-聚酰胺的发夹共轭物定制为靶向特定DNA序列：非手性CI部分与腺嘌呤-N3（一叠咪唑）选择性反应/苯并呋喃优选G / C碱基对，吡咯/苯并呋喃优选A / T或T / A碱基对。发夹结合物1-3与序列5'结合的模型

  DOI：

  10.1016/j.bmcl.2005.04.006

文献信息

• Compositions and methods of the use thereof achiral analogues of CC-1065 and the duocarmycins
  申请人：——

  公开号：US20030073731A1

  公开（公告）日：2003-04-17

  The present invention relates to novel achiral seco-analogues of the DNA minor groove and sequence-selective alkylating agents (+)-CC1065 and the duocarmycins, depicted as general class I, II III, IV and V: 1 wherein X is a good leaving group, such as a chloride, a bromide, an iodide, a mesylate, a tosylate, an acetate, a quaternary ammonium moiety, a mercaptan, an alkylsulfoxyl, or an alkylsulfonyl group, preferably either a chloride, a bromide, or an iodide group. R 1 is a suitable minor groove binding agent to enhance the interactions of the achiral seco-cyclopropaneindole (CI) or an achiral seco-duocarmycin with specific sequences of DNA. Examples of the DNA binders are given in Table 4. The preferred DNA binders are groups A, C, D, E, F, G. H and I. R 1 can also include the following: t-butoxy, benzyloxy, 9-fluorenylmethyloxy or other common protecting groups for amines wherein X is a good leaving group, such as a chloride, a bromide, an iodide, a mesylate, a tosylate, an acetate, a quaternary ammonium moiety, a mercaptan, an alkylsulfoxyl, or an alkylsulfonyl group, preferably either a chloride, a bromide, or an iodide group. R 1 is a suitable minor groove binding agent to enhance the interactions of the covalently reactive achiral seco-pharmacophore with specific sequences of DNA. Examples of the DNA binders are given in Table 4. The preferred DNA binders are groups A, C, D, E, F, G, H, I, J, K and L. R 2 and R 3 can be hydrogen or short chain alkyl (C1-C5) groups, preferably both being hydrogen atoms. The alkyl groups may be straight chain or branched and include such groups as ethyl, propyl, butyl, pentyl and hexyl. R 4 and R 5 can be hydrogen atoms, short alkyl groups, trifluoromethyl moieties, and alkyloxycarbonyl groups. The preferred R 4 and R 5 groups are methoxycarbonyl and trifluoromethyl. R can be either a benzyl, a benzyloxycarbonyl, a hydrogen atom, a 4-nitrobenzyloxycarbonyl, or a N′-methylpiperazinyl-N-carbonyl group wherein X is a good leaving group, R 1 is a minor groove binding agent, such as the binding units of adozelesin and duocarmycins, netropsin and bisbenzimide. R 2 and R 3 can be hydrogen or short-chain alkyl (C1-C5) groups. R 4 and R 5 can be hydrogen atoms, short alkyl groups, trifluoromethyl moieties, and alkyloxycarbonyl groups. R can be either a benzyl, a benzyloxycarbonyl, a hydrogen atom, a 4-nitrobenzyloxycarbonyl, or a N′-methylpiperazinyl-N-carbonyl group. The present invention is further directed to pharmaceutical compositions thereof, and as a method for treatment of cancer using the subject compounds.

  本发明涉及DNA次要沟槽和序列选择性烷基化剂（+）-CC1065和二聚卡霉素的新型无手性截断类似物，表示为一般的I、II、III、IV和V类：其中X是一个良好的离去基团，例如氯化物、溴化物、碘化物、甲磺酸酯、对甲苯磺酸酯、乙酸酯、季铵盐基团、巯基、烷基亚砜基或烷基砜基，最好是氯化物、溴化物或碘化物基团。R1是适合的次要沟槽结合剂，用于增强无手性截断环丙烯吲哚（CI）或无手性截断二聚卡霉素与DNA特定序列的相互作用。DNA结合剂的示例见表4。首选的DNA结合剂是A、C、D、E、F、G、H和I组。R1还可以包括以下内容：叔丁氧基、苄氧基、9-芴甲氧基或其他常见的胺保护基，其中X是一个良好的离去基团，例如氯化物、溴化物、碘化物、甲磺酸酯、对甲苯磺酸酯、乙酸酯、季铵盐基团、巯基、烷基亚砜基或烷基砜基，最好是氯化物、溴化物或碘化物基团。R1是适合的次要沟槽结合剂，用于增强共价反应性无手性截断药物基团与DNA特定序列的相互作用。DNA结合剂的示例见表4。首选的DNA结合剂是A、C、D、E、F、G、H、I、J、K和L组。R2和R3可以是氢或短链烷基（C1-C5）基团，最好两者都是氢原子。烷基基团可以是直链或支链，并包括乙基、丙基、丁基、戊基和己基等基团。R4和R5可以是氢原子、短烷基基团、三氟甲基基团和烷氧羰基基团。首选的R4和R5基团是甲氧羰基和三氟甲基。R可以是苄基、苄氧羰基、氢原子、4-硝基苄氧羰基或N'-甲基哌嗪基-N-羰基基团，其中X是一个良好的离去基团，R1是一个次要沟槽结合剂，例如阿多泽林和二聚卡霉素、奈曲霉素和双苯并咪啉的结合单元。R2和R3可以是氢或短链烷基（C1-C5）基团。R4和R5可以是氢原子、短烷基基团、三氟甲基基团和烷氧羰基基团。R可以是苄基、苄氧羰基、氢原子、4-硝基苄氧羰基或N'-甲基哌嗪基-N-羰基基团。本发明还涉及其制药组合物，以及使用所述化合物治疗癌症的方法。
• COMPOSITIONS AND METHODS OF THE USE THEREOF ACHIRAL ANALOGUES OF CC-1065 AND THE DUOCARMYCINS
  申请人：TAIHO PHARMACEUTICAL CO., LTD.

  公开号：EP1320522B1

  公开（公告）日：2005-11-23
• US6660742B2
  申请人：——

  公开号：US6660742B2

  公开（公告）日：2003-12-09
• DNA interstrand crosslinking agents: Synthesis, DNA interactions, and cytotoxicity of dimeric achiral seco-amino-CBI and conjugates of achiral seco-amino-CBI with pyrrolobenzodiazepine (PBD)
  作者：Bethany Purnell、Atsushi Sato、Amanda O’Kelley、Carly Price、Kaitlin Summerville、Stephen Hudson、Caroline O’Hare、Konstantinos Kiakos、Tetsuji Asao、Moses Lee、John A. Hartley

  DOI：10.1016/j.bmcl.2006.08.005

  日期：2006.11

  The design and synthesis of three novel bisalkylating agents derived from the achiral seco-duocarmycin or CC-1065 analogs and pyrrolobenzodiazepines (PBDs) are described: achiral seco-CBI (cyclopropanebenz[e]indoline)-PBD 11, achiral seco-CI-PBD 12, and achiral seco-CBI dimer 13. Compounds 11 and 12 demonstrated enhanced cytotoxicity over the monomer counterparts against the growth of PS 15 murine mastocytoma cells in culture. Conjugate 11 was found to covalently react with adenine-N3 positions within the minor groove at AT-rich sequences and to produce DNA interstrand crosslinks. Both compounds were found to induce apoptosis in P815 cells. Due to its poor water solubility, dimer 13 did not give any appreciable DNA binding or cytotoxicity. (c) 2006 Elsevier Ltd. All rights reserved.
• Sequence specific recognition of DNA by tailor-made hairpin conjugates of achiral seco-cyclopropaneindoline-2-benzofurancarboxamide and pyrrole–imidazole polyamides
  作者：Carly A. Price、Brian M. Lingerfelt、Heather L. Handl、Konstantinos Kiakos、John A. Hartley、Moses Lee

  DOI：10.1016/j.bmcl.2005.04.006

  日期：2005.6

  gamma-aminobutyrate group, were synthesized. The sequence-specific covalent alkylation of the achiral CI moiety with adenine-N3 in the minor groove was ascertained by thermally induced DNA cleavage experiments. The results provide evidence that hairpin conjugates of achiral seco-CI-Bf-gamma-polyamides could be tailored to target specific DNA sequences according to a set of general rules: the achiral CI moiety selectively

  由γ-氨基丁酸酯连接的非手性癸二酸环丙烷二氢-2-苯并呋喃甲酰胺（非手性Seco-CI-Bf）和三种二酰胺（ImPy 1，PyIm 2和PyPy 3，其中Py为吡咯，Im为咪唑）的发夹共轭物组，进行了合成。通过热诱导DNA切割实验确定在小沟中非手性CI部分与腺嘌呤-N3的序列特异性共价烷基化。结果提供了证据，可以根据一组通用规则将非手性seco-CI-Bf-γ-聚酰胺的发夹共轭物定制为靶向特定DNA序列：非手性CI部分与腺嘌呤-N3（一叠咪唑）选择性反应/苯并呋喃优选G / C碱基对，吡咯/苯并呋喃优选A / T或T / A碱基对。发夹结合物1-3与序列5'结合的模型