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标题:Synthesis of novel 7-azaindole derivatives containing pyridin-3-ylmethyl dithiocarbamate moiety as potent PKM2 activators and PKM2 nucleus translocation inhibitors
时间:2020-07-07 21:50:20
DOI:10.1016/j.ejmech.2019.03.003
大小:2838 kb
页数:16 PAGES
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目录:
  • Synthesis of novel 7-azaindole derivatives containing pyridin-3-ylmethyl dithiocarbamate moiety as potent PKM2 activators a ...
    • 1. Introduction
    • 2. Results and discussion
      • 2.1. Optimization strategy
        • 2.1.1. Substitution of 1-nitrogen of 7-azaindole ring
        • 2.1.2. Introduction of substitutions on 7-azaindole ring
        • 2.1.3. Replacing 7-azaindole ring with 7-azaindole-like heterocyclic rings
      • 2.2. SAR investigation and anti-proliferation activities
      • 2.3. Preliminary in vivo antitumor efficacy of 6f in the A375 xenograft model
      • 2.4. Synthetic chemistry
        • 2.4.1. Preparation of 7a-7o
        • 2.4.2. Preparation of 16a-16c
      • 2.5. Compound 6f reduces the nuclear translocation of PKM2
      • 2.6. Compound 6f could induce cellular apoptosis and autophagy
      • 2.7. Effects of compound 6f on tumor cell migration
    • 3. Conclusion
    • 4. Experimental section
      • 4.1. General
      • 4.2. General procedure for the synthesis of compounds 6a-6o and 15a-15c
        • 4.2.1. 3-(1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropyl (pyridin-3-ylmethyl)carbamodithioate (6a)
        • 4.2.2. 3-(1-Cyclobutyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropy l(pyridin-3-ylmethyl)carbamodithioate (6b)
        • 4.2.3. 3-(1-Cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropyl (pyridin-3-ylmethyl)carbamodithioate (6c)
        • 4.2.4. 3-Oxo-3-(1-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propyl (pyridin-3-ylmethyl)carbamodithioate (6d)
        • 4.2.5. 3-Oxo-3-(1-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propyl (pyridin-3-ylmethyl) carbamodithioate (6e)
        • 4.2.6. 3-(1-(2,2-Difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropyl (pyridin-3- ylmethyl)carbamodithioate (6f)
        • 4.2.7. 3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropyl (pyridin-3-ylmethyl)carbamodithioate (6g)
        • 4.2.8. 3-(4-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropyl (pyridin-3-ylmethyl)carbamodithioate (6h)
        • 4.2.9. 3-(4-Cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropyl (pyridin-3-ylmethyl) carbamodithioate (6i)
        • 4.2.10. 3-(4-Ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropyl (pyridin-3-ylmethyl)carbamodithioate (6j)
        • 4.2.11. 3-Oxo-3-(4-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propyl (pyridin-3-ylmethyl)carbamodithioate (6k)
        • 4.2.12. 3-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropyl (pyridin-3-ylmethyl)carbamodithioate (6l)
        • 4.2.13. 3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropyl (pyridin-3-ylmethyl)carbamodithioate (6m)
        • 4.2.14. 3-(6-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropyl (pyridin-3-ylmethyl)carbamodithioate (6n)
        • 4.2.15. 3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopropyl (pyridin-3-ylmethyl)carbamodithioate (6o)
        • 4.2.16. 3-Oxo-3-(pyrazolo[1,5-a]pyridin-3-yl)propyl (pyridin-3-ylmethyl)carbamodithioate (15a)
        • 4.2.17. 3-Oxo-3-(pyrazolo[1,5-b]pyridazin-3-yl)propyl (pyridin-3-ylmethyl)carbamodithioate (15b)
        • 4.2.18. 3-Oxo-3-(2-phenylpyrazolo[1,5-b]pyridazin-3-yl)propyl (pyridin-3-ylmethyl)carbamodithioate (15c)
      • 4.3. Synthesis of 7-azaindole derivatives
        • 4.3.1. General procedure for the synthesis of compounds 8g, 8h and 8l
        • 4.3.2. Synthesis of compounds 8a, 8b and 8f
        • 4.3.3. Synthesis of compound 8c
        • 4.3.4. Synthesis of compounds 8d and 8e
        • 4.3.5. Synthesis of compound 8i
        • 4.3.6. Synthesis of compound 8j
        • 4.3.7. Synthesis of compounds 8k and 8m
        • 4.3.8. Synthesis of compounds 8n and 8o
      • 4.4. Synthesis of acetylated heteroaryl cycles
        • 4.4.1. 1-(Pyrazolo[1,5-a]pyridin-3-yl)ethenone (16a) [43]
        • 4.4.2. 1-(Pyrazolo[1,5-b]pyridazin-3-yl)ethanone (16b) [42]
        • 4.4.3. 1-(2-Phenylpyrazolo[1,5-b]pyridazin-3-yl)ethanone (16c) [42]
      • 4.5. Biological assay
      • 4.6. Anti-proliferation activity assay
      • 4.7. High content screening for immunostaining assay
      • 4.8. Apoptosis detected by Annexin V and PI staining
      • 4.9. Migration and proliferation rate assay
      • 4.10. In vivo anticancer activity
      • 4.11. Molecular docking simulation
    • Acknowledgement
    • Appendix A. Supplementary data
    • References

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