有机化学 ›› 2022, Vol. 42 ›› Issue (2): 543-556.DOI: 10.6023/cjoc202107002 上一篇    下一篇

研究论文

二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶酮的合成及生物活性研究

曾艳a,b, 聂礼飞a, 牛超a, 阿依提拉•麦麦提江a,b, Khurshed Bozorova, 赵江瑜a, 阿吉艾克拜尔•艾萨a,b,*()   

  1. a 中国科学院新疆理化技术研究所 新疆特有药用资源利用重点实验室 乌鲁木齐 830011
    b 中国科学院大学 北京 100049
  • 收稿日期:2021-07-02 修回日期:2021-09-06 发布日期:2022-02-24
  • 通讯作者: 阿吉艾克拜尔•艾萨
  • 基金资助:
    中国科学院西部之光(2018-XBQNXZ-B-004)

Synthesis and Biological Activities of Dihydrooxazolo[5,4-d]-pyrrolo[1,2-a]pyrimidinones

Yan Zenga,b, Lifei Niea, Chao Niua, Aytilla Mamatjana,b, Khurshed Bozorova, Jiangyu Zhaoa, Haji Akber Aisaa,b()   

  1. a State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011
    b University of Chinese Academy of Sciences, Beijing 100049
  • Received:2021-07-02 Revised:2021-09-06 Published:2022-02-24
  • Contact: Haji Akber Aisa
  • Supported by:
    West Light Foundation of Chinese Academy of Sciences(2018-XBQNXZ-B-004)

以天然产物脱氧鸭嘴花酮生物碱为基础, 通过生物电子等排手段, 设计并合成了40个二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶酮类化合物, 其结构经1H NMR、13C NMR和HRMS进行了确证, 并对该类化合物合成方法的关键步骤影响因素和构效关系进行了探讨. 使用噻唑蓝(MTT)法对该系列化合物的3种肿瘤细胞(MCF-7、Hela、A549)的体外抗肿瘤活性进行了研究, 采用琼脂打孔法对该系列化合物的抑菌活性也进行了初步评价. 结果表明, 2-(萘-1-基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E12)和2-(4-(三氟甲氧基)苯基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E39)对HeLa和MCF-7有较强的抗肿瘤增殖活性, 半抑制浓度(IC50)值分别为(4.59±0.10)和(6.89±1.26) μmol•L–1; 2-((3R,5R,7R)-金刚烷基-1-基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E6)和2-(3,5-二氯苯基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E28)对白色念珠菌(C. albicans)、大肠杆菌(E. coli)和金黄色葡萄球菌(S. aureus)有较好的抑菌活性.

关键词: 噁唑并嘧啶酮, 合成, 生物电子等排, 抗肿瘤活性, 抗菌活性, 构效关系

Based on the general framework of natural alkaloid deoxyvasicinone, forty dihydrooxazolo[5,4-d]pyrrolo[1,2-a]- pyrimidinone compounds were designed and synthesized through bioisosterism strategy. The novel compounds were confirmed by 1H NMR, 13C NMR and HRMS spectra. The main factors affecting the reactions of synthesis and the structure-activity relationships (SARs) were investigated. The activities of the target compounds against three cancer cell lines (MCF-7, HeLa and A549) were evaluated by methyl thiazolyl tetrazolium (MTT) in vitro. All the compounds were also evaluated for their antimicrobial activities by agar punch method. The results showed that 2-(naphthalen-1-yl)-6,7-dihydrooxazolo[5,4-d]- pyrrolo[1,2-a]pyrimidin-9(5H)-one (E12) and 2-(4-(trifluoromethoxy)phenyl)-6,7-dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidin-9(5H)-one (E39) exhibited relatively better anti-proliferative activities against HeLa and MCF-7 cancer cell lines, with the half maximal inhibitory concentration (IC50) values of (4.59±0.10), (6.89±1.26) μmol•L–1, respectively. 2-((3R,5R,7R)- Adamantan-1-yl)-6,7-dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidin-9(5H)-one (E6) and 2-(3,5-dichlorophenyl)-6,7-dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidin-9(5H)-one (E28) showed good antimicrobial activity to C. albicans, E. coli and S. aureus.

Key words: oxazopyrimidinone, synthesis, bioisosterism, anticancer activity, antimicrobial activity, structure-activity relationships (SARs)