2. Academic Validation
  3. Design and synthesis of β-carboline derivatives with nitrogen mustard moieties against breast cancer

Design and synthesis of β-carboline derivatives with nitrogen mustard moieties against breast cancer

  • Bioorg Med Chem. 2021 Sep 1:45:116341. doi: 10.1016/j.bmc.2021.116341.
Jianan Sun 1,  Jiesen Wang 1,  Xinyan Wang 1,  Xu Hu 1,  Hao Cao 2,  Jiao Bai 3,  Dahong Li 4,  Huiming Hua 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
  • 2 School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
  • 3 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: baijiao@hotmail.com.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: lidahong0203@163.com.
  • 5 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: huimhua@163.com.
PMID: 34365102 DOI: 10.1016/j.bmc.2021.116341
Abstract

To discover the promising antitumor agents, a series of β-carboline derivatives with nitrogen mustard moieties were designed and synthesized. Most target derivatives showed antiproliferative activity against MCF-7 and MDA-MB-231 cells. Among them, (1-methyl-9H-pyrido[3,4-b]indol-3-yl)methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-formamidopropanoate possessed the most potent antiproliferative activity with IC50 values of 1.79 μM and 4.96 μM, respectively, which were significantly higher than that of the parent compounds, and the efficacy was comparable to that of the positive control doxorubicin. More importantly, it showed weak cytotoxicity against human normal breast cell line MCF-10A (IC50 > 20 μM), exhibiting certain selectivity. Subsequently, further mechanism exploration indicated that it induced G2/M phase cell cycle arrest and Apoptosis in MDA-MB-231 cells. The DCFH-DA fluorescent probe assay and comet assay showed that this compound could cause intracellular ROS accumulation and DNA damage. In addition, it exerted potent inhibitory effect on the migration, invasion and adhesion of MDA-MB-231 cells in vitro. In short, (1-methyl-9H-pyrido[3,4-b]indol-3-yl)methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-formamidopropanoate was considered as a promising compound for anti-breast Cancer.

Keywords

Apoptosis; Breast cancer; Nitrogen mustard; β-carboline.

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