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  3. Shikonin N-benzyl matrinic acid ester derivatives as novel telomerase inhibitors with potent activity against lung cancer cell lines

Shikonin N-benzyl matrinic acid ester derivatives as novel telomerase inhibitors with potent activity against lung cancer cell lines

  • Bioorg Med Chem Lett. 2022 Feb 1:57:128503. doi: 10.1016/j.bmcl.2021.128503.
Hongwei Han 1,  Cong He 2,  Xingyu Chen 2,  Yuelin Luo 2,  Minkai Yang 2,  Zhongling Wen 2,  Jiabao Hu 2,  Faxiang Lin 2,  Mi Han 2,  Tongming Yin 3,  Rongwu Yang 2,  Hongyan Lin 4,  Jinliang Qi 5,  Yonghua Yang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
  • 3 Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: linhy@nju.edu.cn.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: qijl@nju.edu.cn.
  • 6 State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: yangyh@nju.edu.cn.
PMID: 34922028 DOI: 10.1016/j.bmcl.2021.128503
Abstract

In this study, a series of novel shikonin N-benzyl matrinic acid ester derivatives (PMMB-299-PMMB-310) were synthesized and tested for their ability to inhibit the proliferation of Cancer cells. Compared with shikonin and matrine, some of the ester derivatives were found to exhibit better anti-proliferative activity against seven different Cancer cell lines, with less cytotoxicity toward non-cancerous cells. The strongest anti-proliferative activity was exhibited by PMMB-302, which had an IC50 value of 2.71 μM against A549 cells. The compound caused cell cycle arrest in the G2/M phase and induced Apoptosis. Effects on the expression of apoptosis-related molecules such as Bcl2, Bcl-xL, Caspase-3, caspase-9 and FADD suggested that PMMB-302 has tumor suppressive roles in lung Cancer cells. In addition, PMMB-302 inhibited expression of Telomerase core proteins, dyskerin and NHP2, and telomerase Reverse Transcriptase RNA. Moreover, molecular docking of PMMB-302 was subsequently conducted to determine the probable binding mode with Telomerase. Taken together, the results indicate that PMMB-302 acts as a tumor suppressor in lung Cancer cells by negatively regulating Telomerase expression.

Keywords

Apoptosis; Cell cycle; Matrine; Shikonin; Telomerase.

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