3,4-bis(3,4-dimethoxyphenyl)-1H-pyrrole-2,5-dione | 653572-66-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 3,4-bis(3,4-dimethoxyphenyl)-1H-pyrrole-2,5-dione
• 英文别名: 3,4-bis(3,4-dimethoxyphenyl)pyrrole-2,5-dione
• CAS: 653572-66-8
• 化学式: C₂₀H₁₉NO₆
• 分子量: 369.374
• InChiKey: HZJYSWGFUMRFAP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  83.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3,4-bis(3,4-dimethoxyphenyl)-1H-pyrrole-2,5-dione 在 氢氧化钾 、 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 生成 3,4-Bis(3,4-dihydroxyphenyl)furan-2,5-dione
  参考文献：
  名称：

  Catechol-Substituted l -Chicoric acid analogues as HIV integrase inhibitors

  摘要：

  HIV integrase catalyzes the integration of HIV DNA copy into the host cell DNA, which is essential for the production of progeny viruses. L-Chicoric acid and dicaffeoylquinic acids, isolated from plants, are well known potent inhibitors of HIV integrase. The common structural features of these inhibitors are caffeic acid derivatives connected to tartaric acid or quinic acid through ester bonds. In the present study, we have synthesized and tested the inhibitory activities of a new type of HIV IN inhibitors, which has catechol groups in place of caffeoyl groups in the structure of L-chicoric acid. Upon substitution of catechol groups at succinic acid, pyrrol dicarboxylic acid, maleimide or maleic anhydride, the inhibitory activities (IC50 = 3.8-23.6 muM) were retained or remarkably increased when compared to parent compound L-chicoric acid (IC50 = 13.7 muM). (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2003.09.046
• 作为产物：
  描述：

  (3,4-dimethoxy-phenyl)-acetic acid-(3,4-dimethoxy-phenacylamide) 在 potassium tert-butylate 、 氧气 作用下， 以 叔丁醇 为溶剂， 反应 2.0h， 生成 3,4-bis(3,4-dimethoxyphenyl)-1H-pyrrole-2,5-dione
  参考文献：
  名称：

  扩展了海洋天然宁格灵B类似物作为P-糖蛋白抑制剂的构效关系研究

  摘要：

  在本研究中，总共合成了25种新的宁格灵B类似物，并评估了它们在过表达P-gp的乳腺癌细胞LCC6MDR中的P-gp调节活性。初步的结构活性研究表明，A环及其两个甲氧基是抑制P-gp活性的重要药效团。在所有衍生物中，23是最有效的P-gp调节剂，在逆转紫杉醇，DOX，长春碱和长春新碱的抗性方面，EC 50为120-165 nM。与维拉帕米相比，选择指数至少大于606相对安全。机理研究表明，化合物23通过抑制P-gp的转运活性来逆转P-gp介导的耐药性，从而恢复细胞内药物的积累。总而言之，我们的研究表明，宁格灵B类似物23是一种无细胞毒性且有效的P-gp化学增敏剂，可在将来用于逆转P-gp介导的临床癌症药物耐药性。

  DOI：

  10.1016/j.ejmech.2016.09.070

文献信息

• Design and Syntheses of Permethyl Ningalin B Analogues: Potent Multidrug Resistance (MDR) Reversal Agents of Cancer Cells
  作者：Pu Yong Zhang、Iris L. K. Wong、Clare S. W. Yan、Xiao Yu Zhang、Tao Jiang、Larry M. C. Chow、Sheng Biao Wan

  DOI：10.1021/jm100035c

  日期：2010.7.22

  A series of novel N-arylalkyl-3,4-diaryl-substituted pyrrole-2,5-diones were synthesized. They exhibited promising P-gp modulating activity in a P-gp overexpressing breast cancer cell line (LCC6MDR). Compound 6 (with three methoxy groups at D-ring) displayed the highest P-gp modulating activity. 6 at 1 mu M can sensitize LCC6MDR cells toward paclitaxel by 18.2-fold. Interestingly, a synergy on modulating P-gp was noted when 6 and 25 were used together (fractional inhibitory concentration index FICI = 0.42). Combination of 6 (0.5 mu M) and 25 (0.5 mu M) resulted in a 66-fold sensitization of LCC6MDR cells toward paclitaxel. They also reversed P-gp mediated doxorubicin (DOX) and vincristine resistance. Kinetic characterization suggests that permethyl ningalin B analogues likely act as a noncompetitive inhibitor of P-gp-mediated DOX transport (K-i = 5.4-5.8 mu M). The present study demonstrates that synthetic analogues of permethyl ningalin B can be employed as effective and safe modulators of P-gp-mediated drug resistance in cancer cells.
• Structure–Activity Relationship Study of Permethyl Ningalin B Analogues as P-Glycoprotein Chemosensitizers
  作者：Jin Wen Bin、Iris L. K. Wong、Xuesen Hu、Zhang Xiao Yu、Li Fu Xing、Tao Jiang、Larry M. C. Chow、Wan Sheng Biao

  DOI：10.1021/jm400930e

  日期：2013.11.27

  A novel series of permethyl ningalin B analogues were synthesized and evaluated for their P-glycoprotein (P-gp)-modulating activities in a P-gp-overexpressing breast cancer cell line (LCC6MDR). Compounds 35 and 37, which possess one methoxy group and one benzyloxy group at aryl ring C, displayed the most potent Pgp-modulating activity. A 1 pM concentration of 35 and 37 resensitized LCC6MDR cells toward paclitaxel by 42.7-fold, with respective EC50 values of 93.5 and 110.0 nM. Their mechanism of P-gp modulation is associated with an increase in intracellular drug accumulation. Their advantages also include low cytotoxicity (IC50 for L929 fibroblast >100 mu M) and high therapeutic indexes (>909 after normalization with their EC50 values). 35 is not a substrate of P-gp. They are potentially dual-selective modulators for both P-gp and breast cancer resistance protein transporters. The present study demonstrates that these new compounds can be employed as effective and safe modulators of Pgp-mediated drug resistance in cancer cells.
• Optimization of permethyl ningalin B analogs as P-glycoprotein inhibitors
  作者：Zhen Wang、Iris L.K. Wong、Fu Xing Li、Chao Yang、Zhen Liu、Tao Jiang、Ting Fu Jiang、Larry M.C. Chow、Sheng Biao Wan

  DOI：10.1016/j.bmc.2015.07.027

  日期：2015.9

  In the present study, a total of 9 novel permethyl ningalin B analogs have been synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast cancer cell line LCC6MDR. Among these derivatives, compound 12 with dimethoxy groups at rings A and B and tri-substitution at ring C with ortho-methoxyethylmorpholine, meta-bromo and para-benzyloxy groups displays the most potent P-gp modulating activity with EC50 of 423 nM to reverse paclitaxel resistance. It is non-toxic towards L929 fibroblast with IC50 greater than 100 mu M and with selective index greater than 236. Its mechanism to reverse P-gp mediated drug resistance is by virtue of inhibiting transport activity of P-gp, restoring intracellular drug accumulation and eventually chemosensitizing the cancer cells to anticancer drug again. Moreover, compound 12 showed better solubility (405 ng/mL) than hit compound 1 in phosphate buffer (pH 4.0). In summary, our study demonstrates that permethyl ningalin B derivative 12 is non-toxic and efficient P-gp inhibitor that is a potential candidate to be used clinically to reverse P-gp mediated cancer drug resistance. (C) 2015 Elsevier Ltd. All rights reserved.
• Catechol-Substituted l -Chicoric acid analogues as HIV integrase inhibitors
  作者：Jae Yeol Lee、Kwon Joong Yoon、Yong Sup Lee

  DOI：10.1016/j.bmcl.2003.09.046

  日期：2003.12

  HIV integrase catalyzes the integration of HIV DNA copy into the host cell DNA, which is essential for the production of progeny viruses. L-Chicoric acid and dicaffeoylquinic acids, isolated from plants, are well known potent inhibitors of HIV integrase. The common structural features of these inhibitors are caffeic acid derivatives connected to tartaric acid or quinic acid through ester bonds. In the present study, we have synthesized and tested the inhibitory activities of a new type of HIV IN inhibitors, which has catechol groups in place of caffeoyl groups in the structure of L-chicoric acid. Upon substitution of catechol groups at succinic acid, pyrrol dicarboxylic acid, maleimide or maleic anhydride, the inhibitory activities (IC50 = 3.8-23.6 muM) were retained or remarkably increased when compared to parent compound L-chicoric acid (IC50 = 13.7 muM). (C) 2003 Elsevier Ltd. All rights reserved.
• Extending the structure−activity relationship study of marine natural ningalin B analogues as P-glycoprotein inhibitors
  作者：Chao Yang、Iris L.K. Wong、Kai Peng、Zhen Liu、Peng Wang、Tingfu Jiang、Tao Jiang、Larry M.C. Chow、Sheng Biao Wan

  DOI：10.1016/j.ejmech.2016.09.070

  日期：2017.1

  In the present study, a total of 25 novel ningalin B analogues were synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast cancer cell line LCC6MDR. Preliminary structure-activity study shows that A ring and its two methoxy groups are important pharmacophores for P-gp inhibiting activity. Among all derivatives, 23 is the most potent P-gp modulator with EC50 of 120–165 nM

  在本研究中，总共合成了25种新的宁格灵B类似物，并评估了它们在过表达P-gp的乳腺癌细胞LCC6MDR中的P-gp调节活性。初步的结构活性研究表明，A环及其两个甲氧基是抑制P-gp活性的重要药效团。在所有衍生物中，23是最有效的P-gp调节剂，在逆转紫杉醇，DOX，长春碱和长春新碱的抗性方面，EC 50为120-165 nM。与维拉帕米相比，选择指数至少大于606相对安全。机理研究表明，化合物23通过抑制P-gp的转运活性来逆转P-gp介导的耐药性，从而恢复细胞内药物的积累。总而言之，我们的研究表明，宁格灵B类似物23是一种无细胞毒性且有效的P-gp化学增敏剂，可在将来用于逆转P-gp介导的临床癌症药物耐药性。