2. Academic Validation
  3. Design, synthesis, and biological activity evaluation of (-)-6-O-desmethylantofine analogues as potent anti-cancer agents

Design, synthesis, and biological activity evaluation of (-)-6-O-desmethylantofine analogues as potent anti-cancer agents

  • Bioorg Med Chem. 2019 Jul 15;27(14):3070-3081. doi: 10.1016/j.bmc.2019.05.030.
Guifang Han 1,  Lihua Qing 2,  Meng Wu 3,  Yuxiang Wang 2,  Yuxiu Liu 3,  Xueling Liu 2,  Ziwen Wang 3,  Jian Ding 2,  Ling-Hua Meng 4,  Qingmin Wang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, PR China; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
  • 2 Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, PR China.
  • 3 State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, PR China.
  • 4 Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, PR China. Electronic address: [email protected].
  • 5 State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, PR China. Electronic address: [email protected].
PMID: 31171403 DOI: 10.1016/j.bmc.2019.05.030
Abstract

Phenanthroindolizidine Alkaloids that possess profound anti-proliferative activity and unique mode of action have recently attracted much attention as potential anti-cancer drug candidates. To intensively study the structure-activity-relationship, we designed, synthesized, and evaluated a series of derivatives of 6-desmethylantofine at C-6 position. Most of the derivatives exhibited potent anti-proliferative activity in BEL-7402 and HL60cells. Compound R-12, the cyanomethyl ether of 6-desmethylantofine, exhibited significant anti-cancer activity and inhibited the proliferation of a panel of 30 Cancer cell lines including 2 multi-drug-resistant cell lines with an average IC50 value of 18.7 nM, which suggests that R-12 is a promising new anti-cancer agent. Our studies suggest that R-12 displayed potent inhibitory effect on cell growth and colony formation, which is associated with delaying S phase progression by inhibiting DNA synthesis in human hepatoma Cancer BEL-7402, SMMC-7721 and ZIP-177 cells.

Keywords

Anti-cancer activity; Anti-cancer mechanism; Phenanthroindolizidine; Structural modification; Structure-activity-relationship.

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