新型葡萄糖-2, 5-二酮哌嗪衍生物的设计、合成与细胞毒活性

doi:10.11978/2022140

热带海洋学报 ›› 2023, Vol. 42 ›› Issue (3): 174-185.doi: 10.11978/2022140CSTR: 32234.14.2022140

新型葡萄糖-2, 5-二酮哌嗪衍生物的设计、合成与细胞毒活性

廖升荣¹^,²(), 许华炎³, 李晓琳¹^,², 刘永宏¹^,²^,³()

1.热带海洋生物资源与生态重点实验室(中国科学院南海海洋研究所), 广东广州 510301
2.中国科学院大学, 北京 100049
3.沈阳药科大学无涯创新学院, 辽宁沈阳 110016

收稿日期:2022-06-21 修回日期:2022-08-01 出版日期:2023-05-10 发布日期:2022-08-18
作者简介:
廖升荣(1979—), 男, 湖南省衡阳市人, 副研究员, 博士, 从事海洋药物的设计与合成
基金资助:
国家自然科学基金面上项目(82073762); 广东省自然科学基金面上项目(2020A1515011045)

Design, synthesis and cytotoxicity of novel glycosyl-2, 5-diketopiperazine derivatives

LIAO Shengrong¹^,²(), XU Huayan³, LI Xiaolin¹^,², LIU Yonghong¹^,²^,³()

1. Key Laboratory of Tropical Marine Bio-resources and Ecology (South China Sea Institute of Oceanology, Chinese Academy of Sciences), Guangzhou 510301, China
2. University of Chinese Academy of Sciences, Beijing 100049, China
3. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China

Received:2022-06-21 Revised:2022-08-01 Online:2023-05-10 Published:2022-08-18
Supported by:
National Natural Science Foundation of China(82073762); Guangdong Basic and Applied Basic Research Foundation(2020A1515011045)

摘要/Abstract

摘要：

从海洋天然产物中挖掘高细胞毒活性化合物成为近年来抗肿瘤药物研究工作的一项重要内容。本研究以2, 5-二酮哌嗪海洋天然产物Piperafizine B为修饰骨架, 在其哌嗪环6位的苄叉邻位引入位阻较大的四乙酰基葡萄糖或葡萄糖基团, 共合成了14个2, 5-二酮哌嗪衍生物(1a-i, 2a-f)。溶解性实验结果初步表明, 相较于Piperafizine B, 衍生物的脂溶性(1.5~27.9mg·mL^-1, 溶剂为二甲亚砜(dimethyl sulfoxide, DMSO))与水溶性(0.1~0.9mg·mL^-1, 溶剂为磷酸缓冲液, pH 7.4)均明显改善。衍生物的细胞毒活性评价结果表明, 部分四乙酰基萄糖衍生物的细胞毒活性较好, 半抑制率浓度值(IC₅₀)为1.0~9.1μmol·L^-1, 并对Huh-7细胞的生长抑制活性具有一定的选择性(3.3~4.5μmol·L^-1)。化合物1c的细胞毒活性最好, 对癌细胞株K562、A549及Huh-7的IC₅₀值分别为1.0、3.6与3.3μmol·L^-1。而将乙酰基水解后的葡萄糖衍生物无明显细胞毒活性(IC₅₀>10μmol·L^-1)。

关键词: 海洋天然产物, 2,5-二酮哌嗪衍生物, 葡萄糖, 结构修饰, 细胞毒

Abstract:

Exploring the cytotoxic compounds from marine natural products is one of the most important tasks for the discovery of anticancer agent in recent years. In this study, based on the marine natural product Piperafizine B, fourteen novel glycosyl-2, 5-diketopiperazine derivatives (1a-i, 2a-f) have been designed and synthesized by the glycosylation on the side phenol group at the 6-position of the 2, 5-diketopiperizine ring. The solubilities of the derivatives are obviously improved in both DMSO (dimethyl sulfoxide, 1.5~27.9mg·mL^-1) and phosphate buffer (0.1~0.9mg·mL^-1, pH=7.4). The cytotoxicity results show that some of the derivatives present good activities with the IC₅₀ values ranging from 1.0~9.1μmol·L^-1, and exhibit selective inhibitory activities on Huh-7 cell lines. Among the derivatives, compound 1c has the best inhibitory abilities on the cell lines K562, A549 and Huh-7 with an IC₅₀values at 1.0, 3.6 and 3.3μmol·L^-1, respectively, while compounds 2a-f have no observable cytotoxicity.

Key words: marine natural product, 2, 5-dikeropiperazine derivative, glucose, modification, cytotoxicity

廖升荣, 许华炎, 李晓琳, 刘永宏. 新型葡萄糖-2, 5-二酮哌嗪衍生物的设计、合成与细胞毒活性[J]. 热带海洋学报, 2023, 42(3): 174-185.

LIAO Shengrong, XU Huayan, LI Xiaolin, LIU Yonghong. Design, synthesis and cytotoxicity of novel glycosyl-2, 5-diketopiperazine derivatives[J]. Journal of Tropical Oceanography, 2023, 42(3): 174-185.

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参考文献 28

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化合物	溶解度/(mg·mL^-1)
化合物	C_DMSO	C_缓冲液
1a	21.5	0.9
1b	11.8	0.4
1c	13.9	0.2
1d	17.0	0.9
1e	12.2	0.5
1f	18.0	0.6
1g	21.2	0.8
1h	17.6	0.5
1i	27.9	0.2
2a	18.3	0.6
2b	12.6	0.1
2c	5.70	0.3
2d	7.20	0.8
2e	1.50	0.2
Piperafizine B	0.10	0.05

新型葡萄糖-2, 5-二酮哌嗪衍生物的设计、合成与细胞毒活性

Design, synthesis and cytotoxicity of novel glycosyl-2, 5-diketopiperazine derivatives

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化合物	IC₅₀/(μmol·mL^-1)
化合物	K562	A549	Huh-7
1a	4.5±0.8	5.2±0.6	3.9±0.9
1b	>10	>10	>10
1c	1.0±0.08	3.6±0.2	3.3±0.4
1d	>10	>10	>10
1e	>10	>10	>10
1f	>10	>10	4.2±0.6
1g	>10	2.9±0.2	3.6±0.6
1h	>10	>10	>10
1i	9.1±1.0	>10	4.5±0.5
2a-e	>10	>10	>10
Piperafizine B	>10	>10	>10
Taxol	0.003±0.0002	0.002±0.0008	0.007±0.0005

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