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有机化学
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有机化学 ›› 2026, Vol. 46 ›› Issue (2): 545-553.DOI: 10.6023/cjoc202507006 上一篇    下一篇

研究论文

氨基酸修饰的孕甾衍生物设计合成及抗肿瘤活性研究

顾运琼a,b, 姚嘉伟a, 钟智薇a, 文舒婷a, 杨坤c, 刘亚璐c, 甘春芳a,*()   

  1. a 南宁师范大学化学与材料学院 广西天然高分子化学与物理重点实验室 广西南宁 530100
    b 玉林师范学院化学与食品科学学院 广西农产资源化学与生物技术重点实验室 广西玉林 537000
    c 弘瑞药业有限公司 山西运城 043600
  • 收稿日期:2025-07-03 修回日期:2025-09-03 发布日期:2025-10-23
  • 通讯作者: 甘春芳
  • 基金资助:
    广西自然科学基金(2023GXNSFAA026399); 广西自然科学基金(2023GXNSFDA026063); 国家自然科学基金(22467017); 广西农业资源化学与生物技术重点实验室开放基金(2022KF04); 大学生创新创业训练计划(S202510603146); 大学生创新创业训练计划(S202410603081); 及南宁师范大学教改(2025JGX064)

Design, Synthesis and Antitumor Activity of Amino Acid-Modified Pregnane Derivatives

Yunqiong Gua,b, Jiawei Yaoa, Zhiwei Zhonga, Shuting Wena, Kun Yangc, Yalu Liuc, Chunfang Gana,*()   

  1. a Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, School of Chemistry and Material, Nanning Normal University, Nanning, Guangxi 530100
    b Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, Yulin, Guangxi 537000
    c Hongrui Pharmaceutical Co., Ltd, Yuncheng, Shanxi 043600
  • Received:2025-07-03 Revised:2025-09-03 Published:2025-10-23
  • Contact: Chunfang Gan
  • Supported by:
    Natural Science Foundation of Guangxi(2023GXNSFAA026399); Natural Science Foundation of Guangxi(2023GXNSFDA026063); National Natural Science Foundation of China(22467017); Open Fund of Guangxi Key Laboratory of Agricultural Resources Chemistry and Biotechnology(2022KF04); Innovation and Entrepreneurship Training Program for College Students(S202510603146); Innovation and Entrepreneurship Training Program for College Students(S202410603081); Nanning Normal University Teaching Reform Project(2025JGX064)

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氨基酸修饰是改善药物溶解性、渗透性和生物活性的有效策略, 在抗肿瘤药物研发中具有重要意义. 以孕烯醇酮为先导化合物, 结合阿比特龙的17-位侧链结构特点, 设计并合成了一系列17-位氨基酸修饰的孕甾衍生物(酯/羧酸形式). 噻唑蓝(MTT)法测试表明, 羧酸形式的衍生物无显著抑制活性, 而酯基形式的衍生物可显著抑制癌细胞增殖. 其中, L-苯丙氨酸衍生物(7h)对SKOV-3细胞的抑制活性(IC50=15.10 µmol/L)显著优于阿比特龙(IC50=59.5 µmol/L); L-脱氧蒜氨酸衍生物(7d)对T47D细胞的活性(IC50=15.46 µmol/L)亦优于阿比特龙(IC50=34.66 µmol/L). 该研究为基于氨基酸修饰的孕甾类抗肿瘤药物设计提供了新思路, 尤其提示酯化修饰对活性的关键作用.

关键词: 孕烯醇酮, 结构修饰, 氨基酸酯衍生物, 抗肿瘤活性

The introduction of amino acid fragments into drug molecules represents a significant strategy in the development of novel antitumor agents. This approach serves to overcome the poor solubility and low permeability of the parent drug, thereby enhancing its biological activity. Based on pregnenolone as the lead compound and incorporating structural features of the clinical drug abiraterone, a series of pregnane derivatives bearing various amino acid fragments at the 17-position side chain were designed and synthesized. The in vitro antitumor activities of the target compounds were evaluated using the thiazolyl blue tetrazolium bromide (MTT) assay. The results indicated that when the amino acid fragment existed in the carboxylic acid form, it exhibited negligible inhibitory activity against cancer cells. Conversely, when present in the ester form, it markedly enhanced the antiproliferative effect on cells. Among the synthesized compounds, the L-phenylalanine derivative (7h) demonstrated promising in vitro antiproliferative activity against the SKOV-3 cell line (IC50=15.10 µmol/L). Similarly, the L-deoxyalliin derivative (7d) showed comparable inhibitory activity against the T47D cell line (IC50=15.46 µmol/L). Notably, both compounds 7h and 7d exhibited superior potency compared to the positive control, abiraterone (IC50 values of 59.5 and 34.66 µmol/L against SKOV-3 and T47D, respectively). These findings provide a theoretical foundation and valuable experimental reference for the development of novel anticancer drugs.

Key words: pregnenolone, structure modification, amino acid ester derivative, antiproliferative activity