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2014 , Vol. 34 >Issue 8: 1573 - 1581

DOI: https://doi.org/10.6023/cjoc201402004

研究论文

螺杂环单羰基姜黄素类似物的合成、晶体结构与抗肿瘤活性研究

  • 吴建章 ,
  • 翁碧霞 ,
  • 仇佩虹 ,
  • 蔡志坚 ,
  • 范蕾 ,
  • 应士龙 ,
  • 张秀华 ,
  • 吴晓萍 ,
  • 梁广
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  • a 温州医科大学药学院 化学生物学研究中心 温州 325035;
    b 温州医科大学附属第一医院药剂科 温州 325000;
    c 暨南大学组织移植与免疫实验中心 广州 510632

收稿日期: 2014-02-05

  修回日期: 2014-04-05

  网络出版日期: 2014-05-05

基金资助

国家自然科学基金（Nos.81272462，81102310）、浙江省自然科学基金（Nos.LY12H30004，Y4090379）、浙江省医药卫生科技计划（No.2012KYA129）、温州市科技局（No.S20100045）、浙江省重点科技创新团队（Nos.2010R50042-04）资助项目

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Synthesis, Crystal Structure, Antitumor Activity of Spiro-heterocyclic Mono-carbonyl Analogues of Curcumin

  • Wu Jianzhang ,
  • Weng Bixia ,
  • Qiu Peihong ,
  • Cai Zhijian ,
  • Fan Lei ,
  • Ying Shilong ,
  • Zhang Xiuhua ,
  • Wu Xiaoping ,
  • Liang Guang
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  • a Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical Universtiy, Wenzhou 325035;
    b Department of Pharmacy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000;
    b Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou 510632

Received date: 2014-02-05

  Revised date: 2014-04-05

  Online published: 2014-05-05

Supported by

Project supported by the National Natural Science Fundation of China (Nos. 81272462, 81102310), the Natural Science Fundation of Zhejiang Province (Nos. LY12H30004, Y4090379), the Technology Foundation for Medical Science of Zhejiang Province (No. 2012KYA129), the Project of Wenzhou Sci-Tech Bureau (No. S20100045), the Zhejiang Provicial Project of Key Scientific Group (No. 2010R50042-04).

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摘要

为了发现新型姜黄素类抗肿瘤先导化合物，通过1，3-偶极环加成反应合成了14个螺杂环单羰基姜黄素类似物. 该反应利用无需加催化剂的“一锅煮”方法合成，具有环境友好的优点. 所有化合物结构经ESI-MS、ESI-HRMS和1H NMR确认，通过X衍射确证B6的晶体结构为单斜晶系，该类化合物的合成具有良好的区域选择性和立体选择性. 通过噻唑兰（MTT）法测定所有化合物对人胃癌细胞SGC-7901、神经胶质瘤细胞U251、人大细胞肺癌细胞株NCI-H460的增殖抑制活性，部分化合物表现出了较好的活性. 其中B1、B6、B7和B11对三种肿瘤细胞均表现出较好的抗肿瘤活性，而对正常人肝细胞HL-7702显示了相对较低的细胞毒性. 化合物B1和B7均能明显诱导凋亡相关蛋白含半胱氨酸的天冬氨酸蛋白水解酶3（caspase3）和多聚ADP-核糖聚合酶（PARP）的活化，诱导肿瘤细胞发生凋亡. 所合成的螺杂环单羰基姜黄素类似物为新型的抗肿瘤化合物，该类化合物可能在靶向抗肿瘤药物研发方面具有较好的研究前景.

关键词： 单羰基姜黄素类似物; 螺杂环; 抗肿瘤; 合成

本文引用格式

吴建章 , 翁碧霞 , 仇佩虹 , 蔡志坚 , 范蕾 , 应士龙 , 张秀华 , 吴晓萍 , 梁广 . 螺杂环单羰基姜黄素类似物的合成、晶体结构与抗肿瘤活性研究[J]. 有机化学, 2014 , 34(8) : 1573 -1581 . DOI: 10.6023/cjoc201402004

Abstract

To discover novel lead compounds with good antitumor activity and low toxicity, 14 spiroheterocycle mono-car- bonyl analogs of curcumin (MCACs) were synthesized by 1,3-dipolar cycloaddition reaction. The one-pot reaction was carried out without catalyst, which showed the advantage of environmentally friendly. The structures of all compounds were characterized by ESI-MS, ESI-HRMS and 1H NMR. The crystal structure of B6 was confirmed as monoclinic system by X-ray diffraction, which indicated high region-selectivity and stereo-selectivity in the reaction of these compounds. All compounds were screened for their abilities to inhibit the growth of human gastric cell SGC-7901, glioma cell U251, human large cell lung cancer cell lines NCI-H460 by thiazolyl blue tetrazolium bromide (MTT) assay, and some of them showed good antitumor activity. Among the active compounds, B1, B6, B7 and B11 exhibited strong antitumor efficacy on the three tumor cells and low cytotoxicity against human liver cells HL-7702. Both compounds B1 and B7 can significantly induce the activation of apoptosis related proteins cysteinyl aspartate specific proteinase (caspase3) and poly ADP-ribose polymerase (PARP), and induce the apoptosis of tumor cell. The synthesized spiro heterocycles derived from MCACs in this study were novel antitumor compounds, and these compounds appeared to possess good research prospect in the area of anti-tumor drugs.

Key words： mono-carbonyl analogs of curcumin; spiro-heterocyclic; antitumor; synthesis

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