title: Novel 1H-pyrazole-3-carboxamide derivatives: synthesis, anticancer evaluation and identification of their DNA-binding interaction.
abstract: 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 (K(pym-5)=1.06×10(5) 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.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Ting
authors.initials: T
authors.lastname: Ran
authors.forename: Guowu
authors.initials: G
authors.lastname: Lin
authors.forename: Qiaomei
authors.initials: Q
authors.lastname: Jin
authors.forename: Jianling
authors.initials: J
authors.lastname: Jin
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Guo
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D004247:DNA; C427203:calf thymus DNA