X. Zhang et al.
InorganicChemistryCommunications94(2018)92–97
Fig. 4. Effects of (TFPPy)PtPic (5 μM 24 h) and (TFPQ)PtPic (5 μM 24 h) on S-phase and G2-phase profiles by flow cytometry. Cells were treated with DMSO (0.1%,
24 h) as blank, with Cisplatin (5 μM 24 h) as control. Data presented were from one of two experiments with similar results.
pyridine-2-carboxylate was chosen rather than more active leaving
group. Thus the two complexes were expected more resistant to ligand
substitution reactions entering physiological environments, side reac-
tions such as binding to macro biomolecules prior to DNA binding will
be minimized to reduce unwanted side effects (Scheme 1).
The synthesis procedure of the two complexes are described in the
ESI2. The complexes are characterized using 1H,19F NMR and mass
spectroscopy. The spectra of (TFPPY)PtPic and (TFPQ)PtPic in DMSO
show phosphorescent emission bands in the range of 565–595 nm at
room temperature, the peak wavelength of 580 nm and 582 nm re-
spectively (Fig. S1). Electron withdrawing fluorine atoms into ancillary
ligand lower the HOMO and LUMO level of the complexes, enlarge the
energy gap (Fig. S2).
CLSM imaging results (Fig. 1) show that (TFPPY)PtPic and (TFPQ)
PtPic are partially held in the membrane and cell plasma, possibly due
to the hydrophobic interactions between the aromatic ligands binding
to the phospholipid bilayer and cytoplasm proteins. After entering cell
membrane, the two complexes are found both enriched at cell nucleus,
co-localize with the commercial nuclear DNA marker Hoechst 33,342
(2′-(4-ethoxyphenyl)-5-(4-methyl-1-piperazinyl)-2,5′-bi-1H-benzimi-
dazole trihydrochloride).
Agree with the imaging results, molecular docking calculations has
shown that (TFPPy)PtPic and (TFPQ)PtPic adopted compact con-
formation to bind in the minor groove of HSV-1 DNA (Fig. 2(a–b)). The
2-phenylpyridine and 2-phenylquinoline ligands were positioned at the
bottom of the minor groove, forming stable hydrophobic bindings,
surrounded by the nucleotides DA-27, DT-66, DG-67 and DG-68, aided
by the electrostatic interactions on the molecule surface (Fig. S3). Im-
portantly, two hydrogen bond interactions are shown between the
(TFPQ)PtPic and the nucleotide DG-68 of the DNA, which was the main
binding affinity between the (TFPQ)PtPic and the DNA (Fig. 2b). In
addition, the estimated binding energies were −7.8 kcal mol−1 for
(TFPPy)PtPic and −8.6 kcal mol−1 for (TFPQ)PtPic, respectively, in-
dicating that (TFPQ)PtPic was more active than (TFPPy)PtPic against
DNA duplex.
Improved IC50 values against various cell lines are found, with
positive control of Cisplatin and Fluorouracil. The anti-proliferation
effects in cancer cell lines should attribute to the DNA-binding cross
links formed by these complexes, interfere with DNA replication.
Hek293 (human embryonic kidney) and Vero (African green monkey)
cell lines were used as normal cell control. Both Pt agents have shown
selectivity against various cancer cell lines in 1–2 order of magnitude
Effects of (TFPPy)PtPic and (TFPQ)PtPic treatment after irradia-
tion were exmained with Eca109 and Eca109R (radiation-resistant
subline) cells, where survival fraction was detected by colony formation
assay after treatment. Reduction in colony formation exhibited in both
complexes treated cells after irradiation, indicating that treatment of
these two complexes promotes the radio-sensitivities. Sensitization
enhancement ratio (SER) was determined by multi target single-hit
model (Fig. 3). Significant radio-sensitizing effects were observed at
increased radiation doses in each group. The calculated SER values of
two complexes against Eca109 and Eca109R cell lines were in the range
2
Electronic Supplementary Information (ESI) available: Experimental details see DOI:
10.1039/c000000x/.
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