2. Academic Validation
  3. Design, synthesis and biological evaluation of novel modified dual-target shikonin derivatives for colorectal cancer treatment

Design, synthesis and biological evaluation of novel modified dual-target shikonin derivatives for colorectal cancer treatment

  • Bioorg Chem. 2023 Oct:139:106703. doi: 10.1016/j.bioorg.2023.106703.
Yudi Ma 1,  Xiaohui Lai 2,  Zhongling Wen 1,  Ziling Zhou 1,  Minkai Yang 1,  Qingqing Chen 1,  Xuan Wang 1,  Feng Mei 1,  Liu Yang 1,  Tongming Yin 3,  Shucun Sun 4,  Guihua Lu 1,  Jinliang Qi 1,  Hongyan Lin 5,  Hongwei Han 6,  Yonghua Yang 7
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; School of Biology and Geography Science, Yili Normal University, Yining 835000, 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.
  • 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; School of Pharmacy, Changzhou University, Changzhou 213164, China. Electronic address: linhy@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: hanhw18@nju.edu.cn.
  • 7 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: 37399615 DOI: 10.1016/j.bioorg.2023.106703
Abstract

Warburg effect provides energy and material essential for tumor proliferation, the reverse of Warburg effect provides insights into the development of a novel anti-cancer strategy. Pyruvate Kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key Enzymes in tumor glucose metabolism pathway that not only contribute to the Warburg effect through accelerating aerobic glycolysis, but also serve as druggable target for colorectal Cancer (CRC). Considering that targeting PKM2 or PDK1 alone does not seem to be sufficient to remodel abnormal glucose metabolism and achieve significant antitumor activity, a series of novel benzenesulfonyl shikonin derivatives were designed to regulate PKM2 and PDK1 simultaneously. By means of molecular docking and antiproliferative screen, we found that compound Z10 could act as the combination of PKM2 activator and PDK1 inhibitor, thereby significantly inhibited glycolysis that reshaping tumor metabolism. Moreover, Z10 could inhibit proliferation, migration and induce Apoptosis in CRC cell HCT-8. Finally, the in vivo anti-tumor activity of Z10 was evaluated in a colorectal Cancer cell xenograft model in nude mice and the results demonstrated that Z10 induced tumor cell Apoptosis and inhibited tumor cell proliferation with lower toxicity than shikonin. Our findings indicated that it is feasible to alter tumor energy metabolism through multi-target synergies, and the dual-target benzenesulfonyl shikonin derivative Z10 could be a potential anti-CRC agent.

Keywords

Colorectal cancer; Glycolysis; Pyruvate dehydrogenase kinase; Pyruvate kinase; Shikonin; Warburg effect.

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