(±)-8-acetonyldihydrocoptisine

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 原小檗碱生物碱及其衍生物
• 英文名称: (±)-8-acetonyldihydrocoptisine
• 英文别名: 1-(5,7,17,19-Tetraoxa-13-azahexacyclo[11.11.0.02,10.04,8.015,23.016,20]tetracosa-1(24),2,4(8),9,15(23),16(20),21-heptaen-14-yl)propan-2-one；1-(5,7,17,19-tetraoxa-13-azahexacyclo[11.11.0.02,10.04,8.015,23.016,20]tetracosa-1(24),2,4(8),9,15(23),16(20),21-heptaen-14-yl)propan-2-one
• 化学式: C₂₂H₁₉NO₅
• 分子量: 377.397
• InChiKey: WFOACGQBBBLAIM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  28
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  57.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (±)-8-acetonyldihydrocoptisine 在 盐酸 、 sodium iodide 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 5.0h， 生成
  参考文献：
  名称：

  Syntheses and structure–activity relationships in cytotoxicities of 13-substituted quaternary coptisine derivatives

  摘要：

  Twenty five 13-substituted quaternary coptisine derivatives were synthesized to test their cytotoxicities against several cancer cell-lines and on intestinal epithelial cell-6 (IEC-6) in vitro to evaluate structure-activity relationship (SAR). Introduction of the alkyl groups into the C-13 position of quaternary coptisine (1) led to significant increase of the cytotoxic activity, while the substitution of arylmethyl groups and others at the same position showed no effect on improving cytotoxicities against the same cancer cell-lines. The cytotoxicities of quaternary 13-alkylcoptisines was significantly reinforced as the length of the aliphatic chain increased, with quaternary 13-n-undecylcoptisine (4l) showing 7, 23, 12, and 9 times, respectively, more active than quaternary coptisine (1) against HCT, A549, Be17402, and C33A, and being 4, 11, 2, and 3 times, respectively, more active than the positive control, fluorouracil (5-FU), against the same cell-lines, by IC50 values. In comparison to quaternary 13-n-undecylcoptisine (4l) and the above references, quaternary 13-n-dodecylcoptisine (4m) almost showed the same cytotoxicities. In contrast with the n-alkyl chains, the arylmethyl substituents at C-13 displayed low cytotoxicity, except for naphthyl rings or phenyl rings with CF3 or methyl substituents. However, their low cytotoxicity could make them useful as drug candidates for other diseases (bowel, etc). (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.09.006
• 作为产物：
  描述：

  氯化黄连碱 、 丙酮 在 sodium hydroxide 作用下， 生成 (±)-8-acetonyldihydrocoptisine
  参考文献：
  名称：

  用作抗溃疡性结肠炎药物的季小ine碱型生物碱有机酸盐的多功能合成方法。

  摘要：

  为了确定哪种更有效地改善目标化合物的脂溶性和探索目标化合物作为抗溃疡性结肠炎（UC）的功效，研究了两种通用的方法来合成季铵盐小ber碱型生物碱的各种有机酸盐。 ）代理商。根据反应结果和最终产物的收率进行的总体评价表明，使用叔（±）-8-酰基甲基二氢小ber碱型生物碱作为关键中间体的合成方法优于使用叔二氢小ber碱型生物碱作为中间体的合成方法。分别以氯化小and碱氯化物和氯化黄连磷酸碱为起始原料合成了十种目标化合物，并使用双重荧光素酶报告基因检测技术在体外x-box结合蛋白1（XBP1）转录活性测定中评估了某些目标化合物的抗UC活性。在10μM的条件下，发现受测化合物可激活XBP1靶标的转录，其转录水平几乎与季铵化黄连的水平相同。还发现合成的目标化合物比季铵小ber碱型生物碱的无机酸盐具有更高的脂溶性。

  DOI：

  10.1080/10286020.2016.1171760

文献信息

• Derivatives Of Protoberberine Biological Alkaloids And Use Of Same Inhibiting Ulcerative Colitis
  申请人：Institute of Materia Medica, Chinese Academy of Medical Sciences

  公开号：US20150031717A1

  公开（公告）日：2015-01-29

  Disclosed are derivatives of protoberberine biological alkaloids or physiologically acceptable salts thereof produced by means of a derivative reaction of a source material of biological alkaline quaternary ammonium salts of protoberberine alkaloids, a preparation method for same and pharmaceutical uses thereof. The derivatives of protoberberine biological alkaloids or the physiologically acceptable salts thereof show activity inhibiting ulcerative colitis and can be used in the preparation of drugs for same.

  本文披露了通过对原生物碱类季铵盐的源材料进行衍生反应而产生的原生物碱类季铵盐的衍生物或其生理上可接受的盐，以及其制备方法和药用用途。原生物碱类季铵盐的衍生物或其生理上可接受的盐显示出抑制溃疡性结肠炎的活性，并可用于制备相应药物。
• Versatile methods for synthesizing organic acid salts of quaternary berberine-type alkaloids as anti-ulcerative colitis agents
  作者：Zhi-Hui Zhang、Jing Li、Hai-Jing Zhang、An-Jun Deng、Lian-Qiu Wu、Zhi-Hong Li、Hong-Rui Song、Wen-Jie Wang、Hai-Lin Qin

  DOI：10.1080/10286020.2016.1171760

  日期：2016.6.2

  Two versatile methods to synthesize kinds of organic acid salts of quaternary berberine-type alkaloids were investigated in order to determine which is more efficient to improve the liposolubility of the target compounds and to explore the efficacy of the target compounds as anti-ulcerative colitis (UC) agents. Overall evaluation according to the reaction results and yields of the final products indicated

  为了确定哪种更有效地改善目标化合物的脂溶性和探索目标化合物作为抗溃疡性结肠炎（UC）的功效，研究了两种通用的方法来合成季铵盐小ber碱型生物碱的各种有机酸盐。 ）代理商。根据反应结果和最终产物的收率进行的总体评价表明，使用叔（±）-8-酰基甲基二氢小ber碱型生物碱作为关键中间体的合成方法优于使用叔二氢小ber碱型生物碱作为中间体的合成方法。分别以氯化小and碱氯化物和氯化黄连磷酸碱为起始原料合成了十种目标化合物，并使用双重荧光素酶报告基因检测技术在体外x-box结合蛋白1（XBP1）转录活性测定中评估了某些目标化合物的抗UC活性。在10μM的条件下，发现受测化合物可激活XBP1靶标的转录，其转录水平几乎与季铵化黄连的水平相同。还发现合成的目标化合物比季铵小ber碱型生物碱的无机酸盐具有更高的脂溶性。
• 黄连碱类生物碱衍生物及其抗溃疡性结肠炎 的用途
  申请人：中国医学科学院药物研究所

  公开号：CN104211709B

  公开（公告）日：2018-09-25

  本发明涉及以黄连碱季铵盐为原料经衍生化反应获得的新的13‑取代黄连碱季铵盐类衍生物、13‑取代二氢黄连碱类生物碱衍生物和13‑取代四氢黄连碱类生物碱衍生物、其制备方法及其药物用途；其药物用途特征是：所述黄连碱类生物碱衍生物或其生理上可接受的盐在分子水平的活性测试实验中分别显示出一定的或较显著的xbp1启动子转录激活效应，是在治疗溃疡性结肠炎方面具有较高药用价值的化合物。
• DERIVATIVES OF PROTOBERBERINE BIOLOGICAL ALKALOIDS AND USE OF SAME INHIBITING ULCERATIVE COLITIS
  申请人：Institute of Mataria Medica, Chinese Academy of Medical Sciences

  公开号：EP2789612B1

  公开（公告）日：2018-08-15
• Synthesis and Structure–Activity Relationships of Quaternary Coptisine Derivatives as Potential Anti-ulcerative Colitis Agents
  作者：Zhi-Hui Zhang、Hai-Jing Zhang、An-Jun Deng、Bo Wang、Zhi-Hong Li、Yang Liu、Lian-Qiu Wu、Wen-Jie Wang、Hai-Lin Qin

  DOI：10.1021/acs.jmedchem.5b00964

  日期：2015.9.24

  Thirty quaternary coptisine derivatives from a synthesized library were found to activate the in vitro transcription of x-box-binding protein 1 (XBP1). Among these, the dihydrocoptisines were demonstrated by in vitro XBP1 transcriptional activity assays and animal experiments to be much more active anti-ulcerative colitis (UC) agents than quaternary coptisines, tetrahydrocoptisines, and the positive control. Unsubstituted dihydrocoptisine exhibited more significant anti-UC efficacy than dihydrocoptisines substituted at the C-8 or C-13 position. The EC50 value of dihydrocoptisine for XBP1 transcriptional activation was 2.25 nM. Dihydrocoptisine exhibited a significant dose effect relationship, as indicated by biomarkers in in vitro and in vivo experiments. According to this study, the starting material's reductive states and the substitution patterns of the dihydrocoptisines were determined to be the critical parameters for modulating their anti-UC efficacy, and the dihydrocoptisine skeleton was designated as the key pharmacophore. The synthesized dihydrocoptisine is a promising lead for developing anti-UC drugs.