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  3. Synthesis, biological activity evaluation and mechanism of action of novel bis-isatin derivatives as potential anti-liver cancer agents

Synthesis, biological activity evaluation and mechanism of action of novel bis-isatin derivatives as potential anti-liver cancer agents

  • Bioorg Med Chem Lett. 2024 Jan 13:99:129613. doi: 10.1016/j.bmcl.2024.129613.
Zhifen Li 1,  Jingbo Ma 2,  Ming Tian 3,  Peng Xia 3,  Xiannian Lv 4,  Rui Hou 5,  Yuke Jiang 2,  Xiaolong Xu 2,  Zhifang Jia 1,  Jigang Wang 6,  Zhijie Li 7
Affiliations

Affiliations

  • 1 School of Chemistry and Chemical Engineering, Shanxi Datong University, Xing Yun Street, Pingcheng District, Datong, Shanxi Province 037009, PR China.
  • 2 Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) Shenzhen, Guangdong 518020, PR China.
  • 3 Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430072, PR China.
  • 4 Department of Geriatrics, Fifth People's Hospital of Datong City, Shanxi Province 2669 Wenxing Road North, Pingcheng District, Datong City 037006, Shanxi, PR China.
  • 5 Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) Shenzhen, Guangdong 518020, PR China; Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia.
  • 6 Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) Shenzhen, Guangdong 518020, PR China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, PR China. Electronic address: [email protected].
  • 7 Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) Shenzhen, Guangdong 518020, PR China. Electronic address: [email protected].
PMID: 38224754 DOI: 10.1016/j.bmcl.2024.129613
Abstract

A series of bis-isatin conjugates with lysine linker were synthesized with the aim of probing their antiproliferative potential. All the newly synthesized derivatives (0-100 μM) were first screened against liver Cancer cell lines(Huh1, H22, Huh7, Hepa1-6, HepG2, Huh6 and 97H) using CCK-8 assay. Results indicated that the derivative 4d exhibited the most potent activity against Huh1 (IC50 = 17.13 µM) and Huh7(IC50 = 8.265 µM). In vivo anti-tumor study showed that compound 4d effectively inhibited tumor growth in Huh1-induced xenograft mouse model; the anti-tumor effect of compound 4d (15 mg/kg) was comparable with sorafenib (20 mg/kg). H&E staining analysis and routine blood test and blood serum biochemistry examination was performed to confirm the safety of compound 4d in xenograft models. The mechanism of action of 4d on tumor growth inhibition was further investigated by RNA-Seq analysis, which indicates a positive regulation of Autophagy signaling pathway, which was further confirmed with key biomarker expression of Autophagy after 4d treatment. Our results suggest that the bis-isatin conjugate compound 4d is a promising tumor inhibitory agent for some liver Cancer.

Keywords

Cancer therapy; Isatin derivatives; Liver cancer; RNA-seq.

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