2. Academic Validation
  3. Synthesis, mechanisms of action, and toxicity of novel aminophosphonates derivatives conjugated irinotecan in vitro and in vivo as potent antitumor agents

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

  • Eur J Med Chem. 2020 Mar 1;189:112067. doi: 10.1016/j.ejmech.2020.112067.
Xiaochao Huang 1,  Meng Wang 2,  Qinghong You 2,  Jing Kong 2,  Haijiang Zhang 2,  Chunhao Yu 2,  Yanming Wang 2,  Hengshan Wang 3,  Rizhen Huang 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huaian, 223003, China; College of Biotechnology, Guilin Medical University, Guilin, 541004, China; State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China. Electronic address: viphuangxc@126.com.
  • 2 Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huaian, 223003, China.
  • 3 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China. Electronic address: whengshan@163.com.
  • 4 College of Biotechnology, Guilin Medical University, Guilin, 541004, China. Electronic address: rzhuang1783@163.com.
PMID: 31972391 DOI: 10.1016/j.ejmech.2020.112067
Abstract

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 μM 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.

Keywords

Aminophosphonate ester; Anti-tumor activity; Apoptosis; Irinotecan.

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