Two zinc (Zn) complexes,
[Zn2(DAT)2Cl4] (I) and
[Zn2(DAT)2(NO3)4] (II), were prepared by grinding
3,5-diamino-1,2,4-triazole (C2H5N5, DAT) with Zn precursors such as ZnCl2 and Zn(NO3)2, respectively. This solid-state reaction gives
the corresponding Zn complex as the sole product in over 99% yield.
This mechanochemical method promotes the selective formation of Zn
complexes different from those obtained using the conventional solution-based
route. The crystal structures of the two complexes were analyzed by
single-crystal X-ray diffraction. Complex (I) crystallizes
in the monoclinic space group P21/c, whereas complex (II) crystallizes in the
triclinic space group P
1̅. Each
complex is characterized by the presence of a characteristic DAT-bridged
dimer with one DAT ligand per Zn atom, and the DAT ligand provides
a bridge between the two Zn metals. All Zn centers of (I) and (II) adopted a slightly distorted tetrahedral
geometry. Both complexes contain a hexanuclear Zn2N4 ring, but their ring structures are different. Complex (I) possesses a boat geometry, while complex (II) has a nearly planar structure. The Zn-bound chlorides of complex
(I) form intermolecular N–H···Cl
hydrogen bonds that link neighboring molecules. In complex (II), the O atoms in the nitrate groups are hydrogen-bonded
to the DAT ligand via O···H–N linkages. Both
complexes exhibit blue emissions in the solid state at ambient temperature.
They were evaluated as anticancer agents in HeLa, NCCIT, and MCF-7
cancer cell lines, exhibiting promising anticancer activities.
Pin1, a cis/trans isomerase of peptidyl-prolyl peptide bonds, plays a crucial role in the pathogenesis of many human cancers. Although chemical inhibitors of Pin1 show potent antitumor therapeutic properties against various cancers, their effect on colorectal cancer, especially colorectal tumor-initiating cells, remains unknown. Here, we investigated the effect of Juglone and KPT6566 on Caco-2 cells and tumor-initiating Caco-2 cells. Juglone and KPT6566 inhibited cell growth and colony formation, and induced apoptosis of Caco-2 cells. We also found that Juglone and KPT6566 downregulated expression of G1-phase-specific cyclins and cyclin-dependent kinases in a time-dependent manner, consistent with suppression of Caco-2 cell proliferation and colony formation. Although tumor-initiating cells are thought to be responsible for resistance to traditional chemotherapeutic drugs, our experiments demonstrate that Juglone or KPT6566 kill both tumor-initiating and non-tumor-initiating Caco-2 cells with equal or similar efficacy. Finally, when CD44+CD133+ tumor-initiating Caco-2 cells were injected into NSG mice, Juglone or KPT6566 led to a meaningful reduction in tumor volume and mass compared with tumors isolated from mice that received control treatment. Overall, these results indicate that chemical Pin1 inhibitors may be a valuable therapeutic option against colorectal tumor-initiating cancer cells.
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