2-[4-amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl acetate | 413577-83-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 2-[4-amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl acetate
• 英文别名: 2-[4-amino-2-[(5,6,7-trimethoxy-1H-indole-2-carbonyl)amino]naphthalen-1-yl]ethyl acetate
• CAS: 413577-83-0
• 化学式: C₂₆H₂₇N₃O₆
• 分子量: 477.517
• InChiKey: RKEHKQZUDQKIKO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  125
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-[4-amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl acetate 在 甲醇 、 potassium carbonate 、 lithium chloride 作用下， 生成 5,6,7-Trimethoxy-1H-indole-2-carboxylic acid [1-(2-chloro-ethyl)-4-methanesulfonylamino-naphthalen-2-yl]-amide
  参考文献：
  名称：

  Efficient Synthesis of Achiral seco-Cyclopropylbenz[2,3-e]indoline Analogues:  [4-Amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl Chloride and [4-Hydroxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl Chloride

  摘要：

  Achiral seco-aminocyclopropylbenz[ 2,3-e] indoline and secohydroxycyclopropylbenz[ 2,3-e] indoline ( seco-CBI) analogues of the duocarmycins and CC-1065, e. g., 7 and 8, are potent anticancer agents. This paper describes significantly improved synthetic strategies for preparing these compounds. Starting from Martius acid ( 9), the new strategy gave a 13-fold increase in the overall yield of 7, and the use of ditertbutyl malonate was economically beneficial. For compound 8, the new strategy employed an Emmons-Horner reaction, followed by a Stobbe condensation, and the overall yield was improved 15-fold.

  DOI：

  10.1021/jo060501o
• 作为产物：
  描述：

  氯硝萘 在 platinum(IV) oxide sodium sulfide 、 sodium hydroxide 、 硫酸 、 硼烷 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢气 、 sodium hydride 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 吡啶 、 乙醇 、 二氯甲烷 为溶剂， 反应 22.5h， 生成 2-[4-amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl acetate
  参考文献：
  名称：

  Efficient Synthesis of Achiral seco-Cyclopropylbenz[2,3-e]indoline Analogues:  [4-Amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl Chloride and [4-Hydroxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl Chloride

  摘要：

  Achiral seco-aminocyclopropylbenz[ 2,3-e] indoline and secohydroxycyclopropylbenz[ 2,3-e] indoline ( seco-CBI) analogues of the duocarmycins and CC-1065, e. g., 7 and 8, are potent anticancer agents. This paper describes significantly improved synthetic strategies for preparing these compounds. Starting from Martius acid ( 9), the new strategy gave a 13-fold increase in the overall yield of 7, and the use of ditertbutyl malonate was economically beneficial. For compound 8, the new strategy employed an Emmons-Horner reaction, followed by a Stobbe condensation, and the overall yield was improved 15-fold.

  DOI：

  10.1021/jo060501o

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。
• A Novel Class of in Vivo Active Anticancer Agents:  Achiral <i>seco</i>-Amino- and <i>seco</i>-Hydroxycyclopropylbenz[<i>e</i>]indolone (<i>seco</i>-CBI) Analogues of the Duocarmycins and CC-1065
  作者：Atsushi Sato、LuAnne McNulty、Kari Cox、Susan Kim、Adrienne Scott、Kristen Daniell、Kaitlin Summerville、Carly Price、Stephen Hudson、Konstantinos Kiakos、John A. Hartley、Tetsuji Asao、Moses Lee

  DOI：10.1021/jm050179u

  日期：2005.6.1

  One achiral seco-hydroxycyclopropylbenz[e]indolone (seco-CBI) (12) and seven achiral seco-amino-CBI (11a-g) analogues of CC-1065 and the duocarmycins were designed, synthesized and evaluated for their DNA-binding and anticancer properties. These compounds contain a core 2-chloroethylnaphthalene structure and they do not have a stereocenter. From thermal cleavage gel analyses, compounds 11a-g and 12 demonstrated similar covalent sequence specificity to adozelesin 3 and the racemic seco-CBI-TMI 4 for binding to the 5'-AAAAA(865)-3' site. Continuous exposure of human (K562) and murine (B16, L1210 and P815) cancer cell lines to the compounds demonstrated their significant cytotoxicity, with IC50 values in the sub-micromolar range. Generally, a good leaving group on the ethyl moiety and a free amino or hydroxyl group on the naphthyl moiety are essential for activity. According to NCI's cytotoxicity screen, compounds 11a and 12 were active against human cancer cell lines derived from lung, colon, melanoma, renal system, and breast. At the respective doses of 15 and 20 mg/kg (administered via an ip route), compounds 11a and 12 inhibited the growth of murine B16-F0 melanoma in C57BL/6 mice, with minimal toxicity, and 11a gave a significant anticancer effect. The in vivo anticancer activity of compound 11a was confirmed in a human tumor xenograft study (advanced stage SC-OVCAR-3 ovarian cancer growing in scid mice). Finally, compound 11a was not toxic to murine bone marrow cell growth in culture at a dose that was toxic for the previously reported compound 4.
• 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
• Efficient Synthesis of Achiral <i>s</i><i>eco</i>-Cyclopropylbenz[2,3-<i>e</i>]indoline Analogues:  [4-Amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl Chloride and [4-Hydroxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl Chloride
  作者：Atsushi Sato、Adrienne Scott、Tetsuji Asao、Moses Lee

  DOI：10.1021/jo060501o

  日期：2006.6.1

  Achiral seco-aminocyclopropylbenz[ 2,3-e] indoline and secohydroxycyclopropylbenz[ 2,3-e] indoline ( seco-CBI) analogues of the duocarmycins and CC-1065, e. g., 7 and 8, are potent anticancer agents. This paper describes significantly improved synthetic strategies for preparing these compounds. Starting from Martius acid ( 9), the new strategy gave a 13-fold increase in the overall yield of 7, and the use of ditertbutyl malonate was economically beneficial. For compound 8, the new strategy employed an Emmons-Horner reaction, followed by a Stobbe condensation, and the overall yield was improved 15-fold.