2-羟基-N-(1,2,3,10-四甲氧基-9-氧代-6,7-二氢-5H-苯并[d]庚搭烯-7-基)乙酰胺 | 74515-40-5

• 分子结构分类: 有机化合物 - 碳氢化合物衍生物 - 环庚三烯酮
• 中文名称: 2-羟基-N-(1,2,3,10-四甲氧基-9-氧代-6,7-二氢-5H-苯并[d]庚搭烯-7-基)乙酰胺
• 英文名称: N-(2-hydroxyacetyl)deacetylcolchicine
• 英文别名: colchifoline；2-hydroxy-N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-6,7-dihydro-5H-benzo[a]heptalen-7-yl]acetamide
• CAS: 74515-40-5
• 化学式: C₂₂H₂₅NO₇
• 分子量: 415.443
• InChiKey: DIELAJDYLJKYSH-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-羟基-N-(1,2,3,10-四甲氧基-9-氧代-6,7-二氢-5H-苯并[d]庚搭烯-7-基)乙酰胺 在 盐酸 作用下， 反应 1.0h， 生成 (1R,7S)-7-chloro-3,3,7-trimethylbicyclo[4.1.0]hept-4-en-1-ol
  参考文献：
  名称：

  Iorio, Maria A.; Molinari, Marisa; Brossi, Arnold, Canadian Journal of Chemistry, 1981, vol. 59, p. 283 - 284

  摘要：

  DOI：
• 作为产物：
  描述：

  秋水仙碱 在 甲醇 、 4-二甲氨基吡啶 、 N-羟基丁二酰亚胺 、 sodium methylate 、 三乙胺 、 三氟乙酸 、 N,N'-二异丙基碳二亚胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 22.25h， 生成 2-羟基-N-(1,2,3,10-四甲氧基-9-氧代-6,7-二氢-5H-苯并[d]庚搭烯-7-基)乙酰胺
  参考文献：
  名称：

  Liposomes as carriers for colchicine-derived prodrugs: Vascular disrupting nanomedicines with tailorable drug release kinetics

  摘要：

  Newly formed tumor vasculature has proven to be an effective target for tumor therapy. A strategy to attack this angiogenic tumor vasculature is to initiate local blood vessel congestion and consequently induce massive tumor cell necrosis. Vascular disrupting agents (VDAs) typically bind to tubulin and consequently disrupt microtubule dynamics. Colchicine and its derivatives (colchicinoids) are very potent tubulin binding compounds but have a narrow therapeutic index, which may be improved by employing a liposomal targeting strategy. However, as a result of their physicochemical properties, colchicinoids are problematic to retain in liposomes, as they are released relatively rapidly upon encapsulation. To overcome this limitation, two hydrolyzable PEGylated derivatives of colchicine were developed for encapsulation into the aqueous core of long-circulating liposomes: a moderately rapid hydrolyzing PEGylated colchicinoid containing a glycolic acid linker (prodrug I), and a slower hydrolyzing PEGylated colchicinoid with a lactic acid linker (prodrug II). Hydrolysis studies at 37 degrees C and pH 7.4 showed that prodrug I possessed relatively rapid conversion characteristics (t(1/2) = 5.4 h) whereas prodrug II hydrolyzed much slower (t(1/2) = 217 h). Upon encapsulation into liposomes, colchicine was released rapidly, whereas both PEGylated colchicine derivatives were efficiently retained and appeared to be released only after cleavage of the PEG-linker. This study therefore demonstrates that, in contrast to colchicine, these novel PEGylated colchicine-derived prodrugs are retained within the aqueous interior after encapsulation into liposomes, and that the release of the active parent can be controlled by using different biodegradable linkers. (C) 2011 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejps.2011.08.027

文献信息

• Reaction of alcohols and amines with diacetyldihydrofluorescein (DADF): Conversion into erythrosine-derivatives on TLC-plates by ammonia and iodine vapors
  作者：Paam N. Sharma、Arnold Brossi

  DOI：10.1002/hlca.19840670136

  日期：1984.2.1

  Reaction of decetylcolchicine (2) and colchifoline (3) with diacetyldihydrofluorescein (1, DADF) afforded the corresponding amide and ester derivatives, converted on TLC-plates after exposure to ammonia and iodine vapors into red colored pigments. This reaction, also observed with DADF-derivatives of codeine, quinine and mescaline is highly sensitive. The red pigment produced from the DADF-ester (6)

  癸基秋水仙碱（2）和秋水仙碱（3）与二乙酰基二氢荧光素（1，DADF）反应，得到相应的酰胺和酯衍生物，在氨和碘蒸气暴露于TLC板上后转化为红色颜料。用可待因，奎宁和甲斯卡林的DADF衍生物也观察到该反应高度敏感。由氨-碘处理形成的秋水仙碱的DADF-酯（6）产生的红色颜料是相应的赤藓红酸酯衍生物。从这些研究中得出的DADF可以用作检测粗混合物中的醇和胺以及进行染料标记的有用试剂。
• Biological effects of modified colchicines. 2. Evaluation of catecholic colchicines, colchifolines, colchicide, and novel N-acyl- and N-aroyldeacetylcolchicines
  作者：Arnold Brossi、Padam N. Sharma、Louise Atwell、Arthur E. Jacobson、Maria A. Iorio、Marisa Molinari、Colin F. Chignell

  DOI：10.1021/jm00364a006

  日期：1983.10

  A series of natural and synthetic colchicine derivatives was examined for their potency in the lymphocytic leukemia P388 screen in mice, for their toxicity in mice, and for their binding to microtubule protein. The natural alkaloids cornigerine and colchifoline and several N,O-substituted analogues of colchifoline were found to be as potent and as toxic as colchicine in the P388 screen with good affinity for tubulin. The 1,2-(methylenedioxy)-substituted isomer of cornigerine was considerably less potent in vivo than could have been anticipated from the in vitro tubulin binding data. Several N-acyl and N-aroyl derivatives prepared from deacetylcolchicine showed high potency in the in vitro and in vivo screens. Colchicide was found to be highly potent in vivo, and N-carbethoxydeacetylcolchicine, a synthetic analogue of colchicine with a N-carbethoxy instead of an N-acetyl function, showed interesting biological properties.
• Synthesis and binding to tubulin of colchicine spin probes
  作者：Padam N. Sharma、Arnold Brossi、J. V. Silverton、Colin F. Chignell

  DOI：10.1021/jm00378a035

  日期：1984.12

  Spin probes of deacetylcholchicine (1), 4-(hydroxymethyl)colchicine (2), and colchifoline (3) have been synthesized to study the binding site for colchicine on tubulin. Acylation of 1-3 with (+/-)-2,2,5,5-tetramethyl-1-pyrrolidinyloxy-3-carboxylic acid (4) afforded diastereomeric mixtures of the esters 5-8 and the amides 9 and 10. Pure diastereomers of 3 were synthesized with 4a and 4b, which inhibited the binding of colchicine by 60%. In the presence of calf brain microtubular protein, the colchifoline spin labels underwent reduction of the nitroxide group, which precluded their use to study the topography of the colchicine binding site.
• Liposomes as carriers for colchicine-derived prodrugs: Vascular disrupting nanomedicines with tailorable drug release kinetics
  作者：Bart J. Crielaard、Steffen van der Wal、Huong Thu Le、Aloïs T.L. Bode、Twan Lammers、Wim E. Hennink、Raymond M. Schiffelers、Marcel H.A.M. Fens、Gert Storm

  DOI：10.1016/j.ejps.2011.08.027

  日期：2012.3

  Newly formed tumor vasculature has proven to be an effective target for tumor therapy. A strategy to attack this angiogenic tumor vasculature is to initiate local blood vessel congestion and consequently induce massive tumor cell necrosis. Vascular disrupting agents (VDAs) typically bind to tubulin and consequently disrupt microtubule dynamics. Colchicine and its derivatives (colchicinoids) are very potent tubulin binding compounds but have a narrow therapeutic index, which may be improved by employing a liposomal targeting strategy. However, as a result of their physicochemical properties, colchicinoids are problematic to retain in liposomes, as they are released relatively rapidly upon encapsulation. To overcome this limitation, two hydrolyzable PEGylated derivatives of colchicine were developed for encapsulation into the aqueous core of long-circulating liposomes: a moderately rapid hydrolyzing PEGylated colchicinoid containing a glycolic acid linker (prodrug I), and a slower hydrolyzing PEGylated colchicinoid with a lactic acid linker (prodrug II). Hydrolysis studies at 37 degrees C and pH 7.4 showed that prodrug I possessed relatively rapid conversion characteristics (t(1/2) = 5.4 h) whereas prodrug II hydrolyzed much slower (t(1/2) = 217 h). Upon encapsulation into liposomes, colchicine was released rapidly, whereas both PEGylated colchicine derivatives were efficiently retained and appeared to be released only after cleavage of the PEG-linker. This study therefore demonstrates that, in contrast to colchicine, these novel PEGylated colchicine-derived prodrugs are retained within the aqueous interior after encapsulation into liposomes, and that the release of the active parent can be controlled by using different biodegradable linkers. (C) 2011 Elsevier B.V. All rights reserved.
• Iorio, Maria A.; Molinari, Marisa; Brossi, Arnold, Canadian Journal of Chemistry, 1981, vol. 59, p. 283 - 284
  作者：Iorio, Maria A.、Molinari, Marisa、Brossi, Arnold

  DOI：——

  日期：——