雌甾羟肟酸衍生物的合成及体外抗肿瘤活性研究

doi:10.6023/cjoc202412017

摘要/Abstract

癌症是全球主要死因之一, 每年导致数百万人死亡, 因此开发高效、低毒的新型抗肿瘤药物至关重要. 本研究以雌酚酮为原料, 通过结构修饰在其17-位引入肟醚键缀合的羟肟酸基团, 合成了一系列雌甾羟肟酸衍生物, 并对其体外抗肿瘤活性进行了评估. 结果表明, 这些羟肟酸缀合的雌甾化合物对多种肿瘤细胞均表现出显著的抑制活性. 其中, O-(N-羟基-己酰胺基)-3-甲氧基-雌酚酮-17-肟(5c)表现出优异的抗肿瘤效果, 进一步研究表明, 5c能够诱导细胞凋亡, 并通过升高细胞内活性氧(ROS)水平导致线粒体损伤, 从而发挥抗肿瘤作用. 研究证实, 羟肟酸基团的引入显著增强了化合物的抗肿瘤活性, 为新型抗肿瘤药物的设计与开发提供了重要参考.

关键词: 羟肟酸, 雌甾, 抗肿瘤活性, 细胞凋亡, 活性氧(ROS)

Cancer continues to be a leading cause of mortality worldwide, claiming millions of lives annually. This underscores the urgent need for the development of highly effective and low-toxicity antitumor agents. In this study, a novel series of steroidal hydroxamic acid derivatives were synthesized through structural modification of estrone. Specifically, an oxime ether-linked hydroxamic acid group was introduced at the 17-position. The in vitro antitumor activity of these compounds was systematically evaluated. The results revealed that the hydroxamic acid-conjugated steroidal derivatives exhibited potent inhibitory effects against a panel of tumor cell lines. Notably, O-(N-hydroxyhexanamido)-3-methoxy-estrophenone-17-oxime (5c) emerged as a standout candidate, demonstrating exceptional antitumor activity. Mechanistic investigations further elucidated that compound 5c induces apoptosis by elevating intracellular reactive oxygen species (ROS) levels, resulting in mitochondrial dysfunction and subsequent cell death. These findings highlight the significant role of the hydroxamic acid moiety in enhancing antitumor efficacy and offer valuable insights for the rational design and development of next-generation antitumor therapeutics.

Key words: hydroxyxamic acid, estrone, anti-tumor activity, apoptosis, reactive oxygen species (ROS)

引用此文

李滢, 梁正会, 钟智薇, 韦幼迎, 刘清然, 展军颜, 甘春芳. 雌甾羟肟酸衍生物的合成及体外抗肿瘤活性研究[J]. 有机化学, 2025, 45(8): 3017-3027.

Ying Li, Zhenghui Liang, Zhiwei Zhong, Youying Wei, Qingran Liu, Junyan Zhan, Chunfang Gan. Synthesis of Estradiol Hydroxamic Derivatives and Their in vitro Antitumor Activities[J]. Chinese Journal of Organic Chemistry, 2025, 45(8): 3017-3027.

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图/表 12

图1. 化合物1~4结构式

Figure 1. Structures of compounds 1~4

图2. 伏立诺他(SAHA)结构式

Figure 2. Structural formula of vorinostat (SAHA)

图3. 化合物5~9结构式

Figure 3. Structures of compounds 5~9

图式1. 合成路线

Scheme 1. Synthesis route

Compd.	Skov-3	MCF-7	Hela	T47D	HepG-2	293T
4a	>80	>80	>80	>80	>80	>80
4b	>80	>80	>80	>80	>80	>80
4c	>80	>80	>80	>80	>80	>80
4d	>80	39.48±1.60	70.90±1.85	>80	>80	>80
4e	>80	>80	51.31±1.71	>80	>80	>80
5a	8.05±0.38	9.76±0.12	8.87±0.28	16.12±0.52	30.52±5.46	15.12±2.64
5b	16.89±0.06	14.26±1.60	16.70±0.16	24.21±0.38	14.33±1.22	28.74±0.62
5c	6.47±0.22	5.54±0.08	6.16±0.14	10.06±0.50	7.43±0.87	18.84±0.44
5d	6.98±0.20	9.54±0.13	13.22±0.36	17.58±0.22	21.52±0.26	19.32±1.92
5e	6.64±0.41	8.59±0.57	6.57±0.37	11.58±0.21	9.22±0.34	15.58±0.70
SAHA^b	0.86±0.06	3.6±0.56	3.20±0.51	—	—	73.91±1.88

表1. 化合物4a~4e和5a~5e对肿瘤细胞72 h的抗增殖活性[(IC50±SD]/(μmol•L－1)a

Table 1. In vitro antiproliferation effects [(IC50±SD]/(μmol•L－1) of compounds 4a~4e and 5a~5e on tumor cells at 72 h

图4. 化合物5c作用Hela细胞72 h抑制率柱状图

Figure 4. Histogram of the inhibition rate of compound 5c on Hela cells for 72 h

图5. 化合物5c作用Hela细胞24 h细胞形态变化图

Figure 5. Cell morphology changes of compound 5c on Hela cells for 24 h

图6. 化合物5c作用Hela细胞24 h细胞划痕(a)变化图和(b)愈合率柱状图

Figure 6. (a) Plot of changes and (b) histogram of cell scratching by compound 5c on Hela cells for 24 h

图7. 化合物5c作用Hela细胞24 h后细胞克隆图

Figure 7. Cell clonogram of the compound 5c on Hela cells for 24 h

图8. (a)化合物5c处理Hela细胞24 h后细胞凋亡图及(b)细胞凋亡变化柱状图

Figure 8. (a) Apoptosis graph of Hela cells treated with compound 5c for 24 h and (b) histogram of apoptosis changes

图9. (a, b) 化合物5c作用Hela细胞24 h后的ROS变化图及(c) ROS变化柱状图

Figure 9. (a, b) ROS plot of compound 5c after 24 h of action on Hela cells, and (c) histogram of ROS changes

图10. (a) 化合物5c处理Hela细胞24 h线粒体膜电位图及(b)线粒体膜电位变化柱状图

Figure 10. (a) Mitochondrial membrane potential of Hela cells treated with compound 5c for 24 h, and (b) histogram of mitochondrial membrane potential change

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