氨基酸修饰的孕甾衍生物设计合成及抗肿瘤活性研究

doi:10.6023/cjoc202507006

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,*

^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
基金资助:
广西自然科学基金(Nos. 2023GXNSFAA026399, 2023GXNSFDA026063), 国家自然科学基金(No. 22467017), 广西农业资源化学与生物技术重点实验室开放基金（2022KF04）和大学生创新创业训练计划资助项目（S202510603146,S202410603081）资助.

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

Gu Yun-Qiong^a,b, Yao Jia-Wei^a, Zhong Zhi-Wei^a, Wen Shu-Ting^a, Yang Kun^c, Liu Ya-Lu^c, Gan Chun-Fang^a,*

^aGuangxi Key Laboratory of Natural Polymer Chemistry and Physics, School of Chemistry and Material, Nanning Normal University, Nanning Guangxi, 530100;
^bGuangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, Yulin, Guangxi 537000, PR China;
^cHongrui Pharmaceutical Co., Ltd, Yuncheng Shanxi, 043600

Received:2025-07-03 Revised:2025-09-03
Contact: *E-mail: gancf@nnnu.edu.cn; ganchunfang2008@126.com
Supported by:
Project supported the National Natural Science Foundation of Guangxi (No. 2023GXNSFAA026399, 2023GXNSFDA026063), the National Natural Science Foundation of China (No. 22467017), the Open Fund of Guangxi Key Laboratory of Agricultural Resources Chemistryand Biotechnology (2022KF04)and the Innovation and Entrepreneurship Training Program for College Students (No. S202410603081).

文章分享

1. cjoc202507006辅助材料.pdf(3137KB)

摘要/Abstract

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。本研究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）。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 µM）显著优于阿比特龙（IC₅₀ = 59.5 µM）;L-脱氧蒜氨酸衍生物（7d）对T47D细胞的活性（IC₅₀ = 15.46 µM）亦优于阿比特龙（IC₅₀ = 34.66 µM）。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, 17-位, 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 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 µM). Similarly, the L-deoxyalliin derivative (7d) showed comparable inhibitory activity against the T47D cell line (IC₅₀= 15.46 µM). Notably, both compounds (7h and 7d) exhibited superior potency compared to the positive control, abiraterone (IC₅₀ values of 59.5 µM and 34.66 µM 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, 17-side, Amino acid ester derivatives, Antiproliferative activity

引用此文

顾运琼, 姚嘉伟, 钟智薇, 文舒婷, 杨坤, 刘亚璐, 甘春芳. 氨基酸修饰的孕甾衍生物设计合成及抗肿瘤活性研究[J]. 有机化学, doi: 10.6023/cjoc202507006.

Gu Yun-Qiong, Yao Jia-Wei, Zhong Zhi-Wei, Wen Shu-Ting, Yang Kun, Liu Ya-Lu, Gan Chun-Fang. Design, Synthesis and Antitumor Activity of Amino Acid-modified Pregnane Derivatives[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202507006.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

参考文献

[1] Kuzminac I. Z.; Nikolić A. R.; Savić M. P.; Ajdukovi J. J.Abiraterone and Galeterone, Powerful Tools Against Prostate Cancer: Present and Perspective[J]. Pharm. 2024, 16(11): 1401-1435.
[2] Capper C. P.; Larios J. M.; Sikora M. J.; Johnson M. D.; Rae J. M.The CYP17A1 inhibitor abiraterone exhibits estrogen receptor agonist activity in breast cancer[J]. Breast. Cancer. Res. Tr. 2016, 157: 23-30.
[3] Stappaerts J.; Geboers S.; Snoeys J.; Brouwers J.; Tack J.; Annaert P.; Augustijns P.Rapid conversion of the ester prodrug abiraterone acetate results in intestinal supersaturation and enhanced absorption of abiraterone: in vitro, rat in situ and human in vivo studies[J]. Eur. J. Pharm. Biopharm. 2015, 90: 1-7.
[4] Bröer S.; Bröer A.Amino acid homeostasis and signalling in mammalian cells and organisms[J]. Biochem. J. 2017, 474(12): 1935-1963.
[5] Vig B. S.; Huttunen K. M.; Laine K. and Rautio J.Amino acids as promoieties in prodrug design and development[J]. Adv Drug. Delive. Rev. 2013, 65(10): 1370-1385.
[6] Zhou Y. Q.; Tian S. C.; Sheng L. X.; Zhang L. Q.; Liu J. J.; Mo W. B.; Cheng K. G.Design, synthesis and in vitro antitumor activity of 17β-estradiol-amino acid derivatives[J]. Arab. J. Chem. 2024, 17(2): 105539.
[7] Yuan W.; Guo J.; Wang X.; Su G.; ,Zhao, Y. Non-protein amino acid derivatives of 25-methoxylprotopanaxadiol/25-hydroxyprotopanaxadioland their anti-tumour activity evaluation[J]. Steroids. 2018, 129: 1-8.
[8] Lin L. Z.; Zhao Y. Q.; Wang ,P.; L, T.; L, Y. H.; C, Y.; M, X. Y. ; Z, Y. D. Amino Acid Derivatives of Ginsenoside AD-2 Induce HepG2 Cell Apoptosis by Affecting the Cytoskeleton[J]. Molecules. 2023, 28(21): 7400-7412.
[9] Tshiluka N. R.; Bvumbi M. V.; Mnyakeni-Moleele, S. S. Synthesis, cytotoxicity and in vitro α-glucosidase inhibition of new N-substituted glitazone and rhodanine derivatives[J]. Russ. J. Bioorg. Chem. 2023, 49(2): 384-389.
[10] Chaves S.; Macías M.; Quevedo R. N-(4-methoxybenzyl)-L-tyrosine ethyl ester: Synthesis, structural analysis, and reaction with formaldehyde[J]. J. Mol. Struct. 2024, 1298: 137079.
[11] Li Y.; Hu N.; Xu Z.; Cui Y.; Feng J.; Yao P.; Ma Y.Asymmetric Synthesis of N‐Substituted 1, 2‐Amino Alcohols from Simple Aldehydes and Amines by One‐Pot Sequential Enzymatic Hydroxymethylation and Asymmetric Reductive Amination[J]. Angew. Chem. 2022, 134(17): e202116344.
[12] Chung H. H.; Kao C. Y.; Wang T. S.A.; Chu, J.; Hsu, C. C. Reaction tracking and high-throughput screening of active compounds in combinatorial chemistry by tandem mass spectrometry molecular networking[J]. Anal. Chem. 2021, 93(4): 2456-2463.
[13] Ozturk P.; Akdag A.Effect of tetraethylene glycol side chain conformation on chiroptical properties of chirality‐induced benzocoumarin[J]. J. Phys. Org. Chem. 2023, 36(2): e4453-e4463.
[14] Caner J.; Matsumoto A.; Maruoka K.Facile synthesis of 1, 2-aminoalcohols via α-C-H aminoalkylation of alcohols by photoinduced hydrogen-atom transfer catalysis[J]. Chem. Sci. 2023, 14(47): 13879-13884.
[15] An Y.; Dong Y.; Liu M.,Han, J. , Zhao, L. ,Sun, B. Novel naphthylamide derivatives as dual-target antifungal inhibitors: Design, synthesis and biological evaluation[J]. Eur. J. Med. Chem. 2021, 210: 112991.
[16] Kim K.; Maharjan S.; Lim C.; Kim N. J.; Agrawal V.; Han Y. T.; Suh Y. G.Glucal-conjugated sterols as novel vascular leakage blocker: Structure-activity relationship focusing on the C17-side chain[J]. Eur. J. Med. Chem. 2014, 75: 184-194.