Cu(II) Complexes with Heterocyclic Substituted Thiosemicarbazones: The Case of 5-Formyluracil. Synthesis, Characterization, X-ray Structures, DNA Interaction Studies, and Biological Activity

Two new 5-formyluracil thiosemicarbazone (H3ut) derivatives, Me-H3ut (1) and Me2-H3ut (2), were synthesized by
reacting thiosemicarbazides, mono- and dimethylated on the aminic nitrogen, with 5-formyluracil and were subsequently
characterized. These ligands, treated with copper chloride and nitrate, afforded three complexes:  [Cu(Me-H3ut)Cl2]·H2O (3), [Cu(Me2-H3ut)Cl2]·H2O (4), and [Cu(Me-H3ut)(NO3)(OH2)2]NO3 (5). The crystal structures of these
complexes have been determined by single-crystal X-ray diffraction. In 3 and 4, a similar pentacoordination is
present; the copper atom is surrounded by the ligand SNO donor atoms and by two chloride ions. The structure
of 5 consists of [Cu(Me-H3ut)(NO3)(OH2)2]+ cations and nitrate anions. The copper coordination (4 + 2) involves the
SNO ligand atoms and a water oxygen in the basal plane; the apical positions are occupied by a second water
oxygen and by an oxygen of a monodentate nitrate group. Two biochemical techniques, namely DNA titration in
the UV−vis region and thermal denaturation, have been employed to probe the details of DNA binding of these
compounds. Analysis of the results suggests that our compounds are able to interact with DNA by electrostatic and
groove binding but not by intercalation. The compounds have been also tested in vitro on human leukemic cell line
U937, but they are not able to inhibit significantly cell proliferation.

本研究合成了两种新型5-甲酰尿嘧啶缩氨基硫脲（H3ut）衍生物，即单甲基取代物Me-H3ut（1）与二甲基取代物Me₂-H3ut（2）：将氨基氮位分别发生单甲基化与二甲基化的氨基硫脲与5-甲酰尿嘧啶反应制备，并对所得产物进行了结构表征。将上述配体分别与氯化铜、硝酸铜反应，得到三种配合物：[Cu(Me-H3ut)Cl₂]·H₂O（3）、[Cu(Me₂-H3ut)Cl₂]·H₂O（4）以及[Cu(Me-H3ut)(NO₃)(H₂O)₂]NO₃（5）。通过单晶X射线衍射解析了这三种配合物的晶体结构。在配合物3与4中，中心铜原子均采取五配位模式，其配位环境由配体提供的SNO配位原子与两个氯离子共同构成。配合物5的晶体结构由[Cu(Me-H3ut)(NO₃)(H₂O)₂]⁺阳离子与硝酸根阴离子组成，该配合物中铜原子的配位模式为（4+2）型：基面配位位点包含配体的SNO配位原子与一个水分子的氧原子，轴向配位位点则由另一个水分子的氧原子与单齿硝酸根的一个氧原子占据。本研究采用紫外-可见光谱DNA滴定法与热变性实验两种生化技术，探究了目标化合物与DNA的结合细节。结果分析表明，所合成的化合物可通过静电相互作用与沟槽结合的方式与DNA相互作用，但无法通过嵌入模式结合DNA。此外，本研究还针对目标化合物开展了人白血病细胞系U937的体外增殖抑制实验，结果显示其无法显著抑制细胞增殖。