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标题:Synthesis and evaluation of N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)nicotinamides as potential anticancer agents that inhibit tubulin polymerization
时间:2019-12-03 20:18:26
DOI:10.1016/j.bmc.2014.04.038
作者:Kamal, Ahmed; Reddy, N.V. Subba; Nayak, V. Lakshma
关键词:E7010; Cell cycle; Cytotoxicity; Triazoles; Tubulin polymerization
出版源: 《Bioorganic & Medicinal Chemistry》 ,22 (13) :3465-3477
摘要:A series of N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)nicotinamides (4) was synthesized and tested for their anticancer activity against a panel of 60 human cancer cell lines. Some of the representative compounds such as 4a, 4b, 4f, 4g, 4i and 4f were selected for the five dose study and amongst them 4g and 4i displayed significant anticancer activity with GI(50) values ranging from 0.25 to 8.34 and 1.42 to 5.86 mu M, respectively. Cell cycle analysis revealed that these compounds induced cell cycle arrest at G2/M phase in MCF-7 cells. The most active compound in this series 4g also inhibited tubulin polymerization with IC50 value 1.93 mu M superior to that of E7010. Moreover, assay to investigate the effect on caspase-9, Hoechst staining and DNA fragmentation analysis suggested that these compounds induced cell death by apoptosis. Docking experiments showed that they interact and bind efficiently with tubulin protein. Overall, the results demonstrate that N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)nicotinamide scaffold possess anticancer property by inhibiting the tubulin polymerization. (C) 2014 Elsevier Ltd. All rights reserved.
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目录:
  • Synthesis and evaluation of N-((1-benzyl-1H-1,2, 3-triazol-4-yl)methyl)nicotinamides as potential anticancer agents that inhibit tubulin polymerization
    • 1 Introduction
    • 2 Results and discussions
      • 2.1 Chemistry
    • 3 Biology
      • 3.1 Cytotoxicity
      • 3.2 Cell cycle analysis
      • 3.3 Effect on tubulin polymerization
      • 3.4 Effect on microtubules
      • 3.5 Hoechst staining for morphological analysis of apoptosis
      • 3.6 Effect on caspase-9
      • 3.7 DNA fragmentation assay
    • 4 Molecular modeling studies
    • 5 Conclusion
    • 6 Experimental section
      • 6.1 Synthesis of 2-chloro-N-(prop-2-ynyl)nicotinamide (6)
      • 6.2 2-(Phenylamino)-N-(prop-2-ynyl)nicotinamide (8a)
      • 6.3 2-(4-Fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (8b)
      • 6.4 2-(4-Chlorophenylamino)-N-(prop-2-ynyl)nicotinamide (8c)
      • 6.5 2-(4-Bromophenylamino)-N-(prop-2-ynyl)nicotinamide (8d)
      • 6.6 2-(4-Methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (8e)
      • 6.7 2-(3-Fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (8f)
      • 6.8 2-(2,4-Dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinam ide(8g)
      • 6.9 2-(2,5-Dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinam ide (8h)
      • 6.10 2-(3,5-Dimethoxyphenylamino)-N-(prop-2-ynyl)nicotina mide (8i)
      • 6.11 N-(Prop-2-ynyl)-2-(3,4,5-trimethoxyphenylamino)nicotin amide (8j)
      • 6.12 2-(4-Chlorobenzylamino)-N-(prop-2-ynyl)nicotinamide (8k)
      • 6.13 N-((1-(3-Phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(phenylamino)nicotinamide (4a)
      • 6.14 2-(4-Fluorophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol4-yl)methyl) nicotinamide (4b)
      • 6.15 2-(4-Chlorophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (4c)
      • 6.16 2-(4-Bromophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (4d)
      • 6.17 2-(4-Methoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (4f)
      • 6.18 2-(3-Fluorophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (4e)
      • 6.19 2-(2,4-Dimethoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (4g)
      • 6.20 2-(2,5-Dimethoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (4h)
      • 6.21 2-(3,5-Dimethoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (4i)
      • 6.22 N-((1-(3-Phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,4,5-trimethoxyphenylamino)nicotinamide(4j)
      • 6.23 N-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-fluorophenylamino)nicotinamide (4k)
      • 6.24 2-(4-Fluorophenylamino)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (4l)
      • 6.25 N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-fluorophenylamino)nicotinamide (4m)
      • 6.26 N-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-methoxyphenylamino) nicotinamide (4n)
      • 6.27 N-((1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-methoxyphenylamino) nicotinamide (4o)
      • 6.28 N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-methoxyphenylamino)nicotinamide (4p)
      • 6.29 2-(2,4-Dimethoxyphenylamino)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide(4q)
      • 6.30 2-(2,4-Dimethoxyphenylamino)-N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (4r)
      • 6.31 N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(2,4-dimethoxyphenylamino)nicotinamide (4s)
      • 6.32 2-(4-Chlorobenzylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (4t)
    • 7 Biology
      • 7.1 Evaluation of in vitro anti-cancer activity
      • 7.2 In vitro growth inhibition
      • 7.3 Cell cycle analysis
      • 7.4 Tubulin polymerization assay
      • 7.5 Immunohistochemistry
      • 7.6 Morphological analysis for apoptosis with Hoechst staining
      • 7.7 Caspase 9 activity
      • 7.8 Determination of the apoptotic DNA Ladder
      • 7.9 Molecular modeling procedure
    • Acknowledgements
    • References and notes

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