Synthesis, mechanisms of action, and toxicity of novel aminophosphonates derivatives conjugated irinotecan in vitro and in vivo as potent antitumor agents

被引：24
作者：
Huang, Xiaochao [1 ,2 ,3 ]
Wang, Meng [1 ]
You, Qinghong [1 ]
Kong, Jing [1 ]
Zhang, Haijiang [1 ]
Yu, Chunhao [1 ]
Wang, Yanming [1 ]
Wang, Hengshan [3 ]
Huang, Rizhen [2 ]
机构：
[1] Huaiyin Inst Technol, Jiangsu Key Lab Reg Resource Exploitat & Med Res, Huaian 223003, Peoples R China
[2] Guilin Med Univ, Coll Biotechnol, Guilin 541004, Peoples R China
[3] Guangxi Normal Univ, State Key Lab Chem & Mol Engn Med Resources, Sch Chem & Pharmaceut Sci, Guilin 541004, Peoples R China
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 189卷
基金：
美国国家科学基金会; 中国国家自然科学基金;
关键词：
Irinotecan; Aminophosphonate ester; Anti-tumor activity; Apoptosis; OXYGEN SPECIES ROS; CELL-CYCLE ARREST; PLATINUM(II) COMPLEXES; TARGETING GROUP; DRUG CONJUGATE; APOPTOSIS; DELIVERY; CANCER; CAMPTOTHECIN; PRODRUG;
D O I：
10.1016/j.ejmech.2020.112067
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Twenty novel aminophosphonates derivatives (5a-5j and 6a-6j) conjugated irinotecan were synthesized through esterification reaction, and evaluated their anticancer activities using MTT assay. In vitro evaluation revealed that they displayed similar or superior cytotoxicity compared to the positive drug irinotecan against A549, MCF-7, SK-OV-3, MG-63, U2OS and multidrug-resistant (MDR) SK-OV-3/CDDP cancer cell lines. Among them, 9b displayed the most potent activity, with IC50 values of 0.92-3.23 mu M against five human cancer cells, which exhibited a 5.4-19.1-fold increase in activity compared to the reference drug irinotecan, respectively. Moreover, cellular mechanism studies suggested that 9b arrested cell cycle at S stage and induced cell apoptosis along with the decrease of mitochondrial membrane potential (MMP). Interestingly, 9b significantly inhibited tumor growth in SK-OV-3 xenograft models in vivo without apparent toxicity, which was better than the positive drug irinotecan. Taken together, 9b possessed potent antitumor activity and may be a promising candidate for the potential treatment of human ovarian cancer cells. (C) 2020 Elsevier Masson SAS. All rights reserved.
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页数：17
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