Chinese Journal of Organic Chemistry ›› 2024, Vol. 44 ›› Issue (5): 1606-1619.DOI: 10.6023/cjoc202311020 Previous Articles     Next Articles

ARTICLES

具更佳成药性的新型三氮烯化合物的设计、合成及抗癌活性研究

许芹芳a, 胡健灵a, 刘园林a, 张超a, 李明月a, 彭姝羚a, 刘志军a,b, 陈河如a,c,d,*()   

  1. a 暨南大学药学院中药及天然药物研究所 中药现代化与创新药物研究国际合作联合实验室 广州 510632
    b 广州药本君安医药科技股份有限公司 广州 510663
    c 广东省中药药效物质基础及创新药物研究重点实验室 广州 510632
    d 暨南大学生物活性分子与成药性优化全国重点实验室 广州 510632
  • 收稿日期:2023-11-22 修回日期:2023-12-20 发布日期:2024-01-18
  • 基金资助:
    广东省自然科学基金(2021A1515011238)

Design, Syntheses of Novel Triazenes with Better Druggability and the Investigation on Their Anti-tumor Activities

Qinfang Xua, Jianling Hua, Yuanlin Liua, Chao Zhanga, Mingyue Lia, Shuling Penga, Zhijun Liua,b, Heru Chena,c,d()   

  1. a International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632
    b Guangzhou PharmCherub Medical Sci. & Tech. Incorporated Corporation, Guangzhou 510663
    c Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou 510632’
    d State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632
  • Received:2023-11-22 Revised:2023-12-20 Published:2024-01-18
  • Contact: *E-mail: thrchen@jnu.edu.cn
  • Supported by:
    Natural Science Foundation of Guangdong Province(2021A1515011238)

Eleven novel 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-alkyl (R2) triazenes have been designed and synthesized. Firstly, 4-aminobenzoic acid, as starting material, underwent diazo reaction following the reaction with methyl alkylamine to build the triazene scaffold. Condensation of carboxylic group with 2-diethylaminoethylamine resulted in all the title compounds. The overall yield of these 3-step reactions was between 46.5% and 68.3%. By using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl- 3-methyl-3-cyclohexyltriazene (6a), 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-phenyltriazene (6e)~1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-methoxyl)benzyltriazene (6j) were confirmed as good broad-spectrum anti-cancer agents again/st human liver cancer cells (HepG-2), rat glioma cells (C6), human colon cancer cells (SW620), human prostate cancer cells (PC-3), murine melanoma cells (B16), and human non-small-cell lung cancer cells (A549). Among them, 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-chloro)phenyltriazene (6g) show- ed as the most active agent, where IC50 values of 6g against C6, SW620, PC-3, and B16 cell lines are less than 10 μmol/L, which is far better than the positive dacarbazine. It was found that when R2 is aryl group with propriate electron-withdrawal intensity, the triazene will have good even excellent anti-cancer activity. Through drug safety evaluation, the safety indexes (SI) of 6e, 6g, and 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-chloro)benzyltriazene (6h) against C6, SW620, and PC-3 cell lines, respectively; 6g, 6h, and 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4- methoxyl)phenyltriazene (6i) against B16 cell line respectively; 6e, 6h, and 6i against HepG-2 cell line respectively; 6i against C6, and SW620 cell lines, respectively; were identified more than 2.0, implied better drug safety than dacarbazine. The partition coefficient (lg P) of 6e, 6g~6i lied between 3.0 and 4.0, meaning good membrane permeability. All the data support that the novel triazenes 6e, 6g~6i have better druggability.

Key words: triazenes, anti-cancer, drug safety evaluation, druggability, drug design-synthesis