{2-[3-(4-morpholinyl)propoxy]-4-nitrophenyl}methanol | 304015-54-1

• 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-[3-(4-morpholinyl)propoxy]-4-nitrophenyl}methanol
• 英文别名: [2-(3-Morpholin-4-ylpropoxy)-4-nitrophenyl]methanol
• CAS: 304015-54-1
• 化学式: C₁₄H₂₀N₂O₅
• 分子量: 296.323
• InChiKey: OQWBBSKLGXQKIE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  87.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  三光气 、 5-amino-1-(chloromethyl)-<(5,6,7-trimethoxyindol-2-yl)carbonyl>-1,2-dihydro-3H-benzindole 、 {2-[3-(4-morpholinyl)propoxy]-4-nitrophenyl}methanol 在 三乙胺 、 二乙酸二丁基锡 作用下， 以 二氯甲烷 为溶剂， 以92%的产率得到[2-(3-morpholin-4-ylpropoxy)-4-nitrophenyl]methyl N-[1-(chloromethyl)-3-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-1,2-dihydrobenzo[e]indol-5-yl]carbamate
  参考文献：
  名称：

  Structure−Activity Relationships for 4-Nitrobenzyl Carbamates of 5-Aminobenz[e]indoline Minor Groove Alkylating Agents as Prodrugs for GDEPT in Conjunction with E. coli Nitroreductase

  摘要：

  Twelve substituted 4-nitrobenzyl carbamate prodrugs of the 5-aminobenz[e]indoline class of DNA minor groove alkylating agents were prepared and tested as prodrugs for gene-directed enzyme prodrug therapy (GDEPT) using a two-electron nitroreductase (NTR) from E. coli B. The prodrugs and effectors were tested in a cell line panel comprising parental and transfected human (SKOV/Skov-NTRneo, WiDr/WiDr-NTRneo), Chinese hamster (V79(puro)/VN79-NTRpuro), and murine (EMT6/EMT6-NTRpuro) cell line pairs. In the human cell line pairs, several analogues bearing neutral methoxyethoxy-, 2-hydroxyethoxy-, or 3-hydroxypropoxy-substituted side chains were good substrates for NTR as measured by cytotoxicity ratios, with NTR-ve/NTR+ve ratios similar to the established NTR substrates CB1954 (an aziridinyl dinitrobenzamide) and the analogous bromomustard. Selectivity for NTR decreased with increasing side-chain size or the presence of a basic amine group. Low to modest selectivity was observed in the Chinese hamster-derived cell line pair; however, in the murine EMT6/EMT6-NTRpuro cell line pair, the above hydroxyalkoxy analogues again showed significant selectivity for NTR. The activity of the 2-hydroxyethoxy analogue was evaluated against NTR-expressing EMT6 tumors comprising ca. 10% NTR+ve cells at the time of tumor treatment. A small decrease in NTR+ve cells was observed after treatment, with a lesser effect against NTR-ve target cells, but these effects were not statistically significant and were much less than for the dinitrobenzamides. These results suggest that useful GDEPT prodrugs based on the 4-nitrobenzyl carbamate and 5-aminobenz[e]indoline motifs may be developed if optimization of pharmacokinetics can be addressed.

  DOI：

  10.1021/jm0205191
• 作为产物：
  描述：

  N-(3-氯丙基)吗啉 在 二异丁基氢化铝 、 potassium carbonate 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 {2-[3-(4-morpholinyl)propoxy]-4-nitrophenyl}methanol
  参考文献：
  名称：

  Structure−Activity Relationships for 4-Nitrobenzyl Carbamates of 5-Aminobenz[e]indoline Minor Groove Alkylating Agents as Prodrugs for GDEPT in Conjunction with E. coli Nitroreductase

  摘要：

  Twelve substituted 4-nitrobenzyl carbamate prodrugs of the 5-aminobenz[e]indoline class of DNA minor groove alkylating agents were prepared and tested as prodrugs for gene-directed enzyme prodrug therapy (GDEPT) using a two-electron nitroreductase (NTR) from E. coli B. The prodrugs and effectors were tested in a cell line panel comprising parental and transfected human (SKOV/Skov-NTRneo, WiDr/WiDr-NTRneo), Chinese hamster (V79(puro)/VN79-NTRpuro), and murine (EMT6/EMT6-NTRpuro) cell line pairs. In the human cell line pairs, several analogues bearing neutral methoxyethoxy-, 2-hydroxyethoxy-, or 3-hydroxypropoxy-substituted side chains were good substrates for NTR as measured by cytotoxicity ratios, with NTR-ve/NTR+ve ratios similar to the established NTR substrates CB1954 (an aziridinyl dinitrobenzamide) and the analogous bromomustard. Selectivity for NTR decreased with increasing side-chain size or the presence of a basic amine group. Low to modest selectivity was observed in the Chinese hamster-derived cell line pair; however, in the murine EMT6/EMT6-NTRpuro cell line pair, the above hydroxyalkoxy analogues again showed significant selectivity for NTR. The activity of the 2-hydroxyethoxy analogue was evaluated against NTR-expressing EMT6 tumors comprising ca. 10% NTR+ve cells at the time of tumor treatment. A small decrease in NTR+ve cells was observed after treatment, with a lesser effect against NTR-ve target cells, but these effects were not statistically significant and were much less than for the dinitrobenzamides. These results suggest that useful GDEPT prodrugs based on the 4-nitrobenzyl carbamate and 5-aminobenz[e]indoline motifs may be developed if optimization of pharmacokinetics can be addressed.

  DOI：

  10.1021/jm0205191

文献信息

• [EN] N-PROTECTED AMINES AND THEIR USE AS PRODRUGS<br/>[FR] AMINES N-PROTEGE ET LEUR UTILISATION EN TANT QUE PROMEDICAMENTS
  申请人：——

  公开号：WO2000064864A9

  公开（公告）日：2001-12-27

  [EN] Compounds of formula (I) or (II), wherein X represents H, C1-6 alkyl or C1-6 alkoxy, said alkyl or alkoxy being optionally substituted with one or more groups; a is 0,1,2,3 or 4; Y represents H or C1-6 alkyl; 1, 2 or 3 of the members Z of the 5-membered aromatic ring are independently selected from -O-, -S-, -N= or -NR-, where R is H or C1-6 alkyl optionally substituted with one or more of groups; and E represents a moiety such that EH is an amine; provided that in formula (I) if a = 0 then Y≠H, are provided along with a method of selecting desired protecting groups by measuring the fragmentation rates of compounds of formula (I) or (II) when the nitro group is selected.
  [FR] L'invention concerne des composés de formule (I) et (II), où X représente H, C1-6 alkyle ou C1-6 alkoxy, ledit alkyle ou alkoxy étant facultativement substitué par au moins un groupe, a est 0, 1, 2, 3, ou 4, Y représente H ou C1-6 alkyle, 1, 2 ou 3 des éléments Z de l'anneau aromatique à 5 branches sont sélectionnés indépendamment parmi -O-, -S-, -N= ou -NR-, où R représente H ou C1-6 alkyle facultativement substitué par au moins un des groupes, et E représente une fraction de telle manière que EH est un amine, étant stipulé que dans la formule (I) si a=0, alors Y≠H. Cette invention concerne également un procédé de sélection de groupes de protection désirées en mesurant les taux de fragmentation des composés de la formule (I) ou (II), quand le groupe nitro est réduit.
• Structure−Activity Relationships for 4-Nitrobenzyl Carbamates of 5-Aminobenz[<i>e</i>]indoline Minor Groove Alkylating Agents as Prodrugs for GDEPT in Conjunction with <i>E. </i><i>c</i><i>oli</i> Nitroreductase
  作者：Michael P. Hay、Graham J. Atwell、William R. Wilson、Susan M. Pullen、William A. Denny

  DOI：10.1021/jm0205191

  日期：2003.6.1

  Twelve substituted 4-nitrobenzyl carbamate prodrugs of the 5-aminobenz[e]indoline class of DNA minor groove alkylating agents were prepared and tested as prodrugs for gene-directed enzyme prodrug therapy (GDEPT) using a two-electron nitroreductase (NTR) from E. coli B. The prodrugs and effectors were tested in a cell line panel comprising parental and transfected human (SKOV/Skov-NTRneo, WiDr/WiDr-NTRneo), Chinese hamster (V79(puro)/VN79-NTRpuro), and murine (EMT6/EMT6-NTRpuro) cell line pairs. In the human cell line pairs, several analogues bearing neutral methoxyethoxy-, 2-hydroxyethoxy-, or 3-hydroxypropoxy-substituted side chains were good substrates for NTR as measured by cytotoxicity ratios, with NTR-ve/NTR+ve ratios similar to the established NTR substrates CB1954 (an aziridinyl dinitrobenzamide) and the analogous bromomustard. Selectivity for NTR decreased with increasing side-chain size or the presence of a basic amine group. Low to modest selectivity was observed in the Chinese hamster-derived cell line pair; however, in the murine EMT6/EMT6-NTRpuro cell line pair, the above hydroxyalkoxy analogues again showed significant selectivity for NTR. The activity of the 2-hydroxyethoxy analogue was evaluated against NTR-expressing EMT6 tumors comprising ca. 10% NTR+ve cells at the time of tumor treatment. A small decrease in NTR+ve cells was observed after treatment, with a lesser effect against NTR-ve target cells, but these effects were not statistically significant and were much less than for the dinitrobenzamides. These results suggest that useful GDEPT prodrugs based on the 4-nitrobenzyl carbamate and 5-aminobenz[e]indoline motifs may be developed if optimization of pharmacokinetics can be addressed.