Novel 1H-Pyrazole-3-carboxamide Derivatives : Synthesis, Anticancer Evaluation and Identification of Their DNA-Binding Interaction

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  • Lu Yi
    State Key Laboratory of Natural Medicines, China Pharmaceutical University
  • Ran Ting
    State Key Laboratory of Natural Medicines, China Pharmaceutical University Laboratory of Molecular Design and Drug Discovery, School of Sciences, China Pharmaceutical University
  • Lin Guowu
    Department of Structural Biology, University of Pittsburgh School of Medicine
  • Jin Qiaomei
    State Key Laboratory of Natural Medicines, China Pharmaceutical University
  • Jin Jianling
    State Key Laboratory of Natural Medicines, China Pharmaceutical University
  • Li Hongmei
    State Key Laboratory of Natural Medicines, China Pharmaceutical University
  • Guo Hao
    State Key Laboratory of Natural Medicines, China Pharmaceutical University
  • Lu Tao
    State Key Laboratory of Natural Medicines, China Pharmaceutical University Laboratory of Molecular Design and Drug Discovery, School of Sciences, China Pharmaceutical University
  • Wang Yue
    State Key Laboratory of Natural Medicines, China Pharmaceutical University State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University

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  • Novel 1<i>H</i>-Pyrazole-3-carboxamide Derivatives: Synthesis, Anticancer Evaluation and Identification of Their DNA-Binding Interaction

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Four novel 1H-pyrazole-3-carboxamide derivatives were synthesized, and their antiproliferative effect on cancer cells, kinase inhibition, and in particular, the DNA-binding interaction were investigated to interpret the antitumor mechanisms. A DNA minor groove binding model was developed, and the binding energy was predicted for the compounds. In consistence with the prediction, the binding ability was determined by the electronic absorption spectroscopy under physiological conditions for the compounds, and further verified by viscosity measurement. One compound 5-(3-cyclopropylureido)-N-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1-H-pyrazole-3-carboxamide (pym-5) exerted the highest DNA-binding affinity (Kpym-5=1.06×105 M−1). And it demonstrated more than 50% decrease of the emission intensity of the ethidium bromide–calf thymus DNA (EB–CT-DNA) complex in fluorescence spectra, suggesting that pym-5 could strongly affect the DNA conformation. Furthermore, pym-5 showed the cleavage activity upon the supercoiled plasmid pBR322 DNA in the pBR322 DNA cleavage assay. Our study suggests that DNA may serve as a potential target to these pyrazole derivatives.

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