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Abstract: Liriodenine (L), an antitumor active ingredient from the traditional Chinese medicine (TCM), Zanthoxylum nitidum, afforded a platinum(II) complex (1) of L, cis-[PtCl2(L)(DMSO)], which previously reported for its in vitro antitumor activity and intercalative binding with DNA. In this study, complex 1 was further discussed for its antitumor mechanism and structure–activity relationship, comparing with L and cisplatin. Towards the most sensitive BEL-7404 human hepatoma cells, complex 1 significantly induced cell cycle arrest at both G2/M phase and S phase. It suggests that double helix DNA is not the simplex intracellular target for 1. On the other hand, the BEL-7404 cells incubated with 1 and stained by Hoechst 33258 and AO/EB showed typical cell apoptosis in dose-dependent manner. The BEL-7404 cells incubated with 1 and stained by JC-1 were also characteristic for cell apoptosis on the loss of mitochondrial membrane potential. Furthermore, the G-quadruplex DNA binding property of complex 1 was also investigated by spectroscopic analyses, fluorescent indicator displacement (FID) assay and fluorescence resonance energy transfer (FRET) assay. The results indicated that 1 stabilized the human telomeric G4-HTG21 DNA better than L. The telomerase inhibition ratio of 1 ((62.50±0.03)%), which was examined by telomerase polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA), was much higher than L ((21.77±0.01)%). It can be ascribed to the better G4-HTG21 DNA stabilization of 1 than L. The results suggested that the nuclei, mitochondria and telomerase via G-quadruplex DNA stabilization all should be key targets for the antitumor mechanism of 1, in which the central platinum(II) played a key role. [Copyright &y& Elsevier]

Abstract: Six new platinum(II) complexes with mono-aminophosphonate ester were synthesized and characterized by elemental analysis, 1H NMR, ESI-MS as well as single crystal X-ray diffraction analysis. They are mononuclear structures. In all the crystal structures of complexes 1–6, the platinum centre adopts an approximately square-planar geometry, which were found to possess excellent solubility in both organic solvents and water and exhibit considerable cytotoxicity against MG-63, SK-OV-3 and HepG2 cell lines, but low cytotoxicity towards normal human liver cell HL-7702. In contrast to cisplatin, their antitumour activities are achieved through the induction of cell apoptosis by G1 cell-cycle arrest. [Copyright &y& Elsevier]

Abstract In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]⋅CH 3 OH (Pt1), [PtClL(DMP)] (Pt2), [PtClL(DPPTH)] (Pt3), [PtClL(PTH)] (Pt4), [PtClL(PIPTH)] (Pt5), [PtClL(PM)] (Pt6) and [PtClL(en)] (Pt7) with 4,4′-dimethyl-2,2′-bipyridine (DMP), 4,7-diphenyl-1,10-phenanthroline (DPPTH), 1,10-phenanthroline (PTH), 2-(1-pyrenecarboxaldehyde) imidazo [4,5-f]-[1,10] phenanthroline (PIPTH), 2-picolylamine (PM) and 1,2-ethylenediamine (en) as telomerase inhibitors and p53 activators. Biological evaluations demonstrated that Pt1 Pt7 exhibited cytotoxic activity against the tested NCI H460, Hep-G2, SK-OV-3, SK-OV-3/DDP and MGC80-3 cancer cell lines, with Pt5 displaying the highest cytotoxicity. Pt5 exhibited an IC 50 value of 0.13 ± 0.16 μM against SK-OV-3/DDP cancer cells and significantly reduced tumor growth in a Hep-G2 xenograft mouse model (tumor growth inhibition (TGI) = 40.8%, p < 0.05) at a dose of 15.0 mg/kg. Interestingly, Pt1 Pt7 displayed low cytotoxicity against normal HL-7702 cells. Mechanistic studies revealed that these compounds caused cell cycle arrest at the G2/M and S phases, and regulated the expression of CDK2, cyclin A, p21, p53 and p27. Further mechanistic studies showed that Pt5 induced SK-OV3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity by directly targeting the c-myc promoter, and activation of the p53 signaling pathway. Taken together, Pt5 has the potential to be further developed as a new antitumor drug. Graphical abstract Pt5 induced SK-OV-3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity and activation of the p53 signaling pathway. Image 1 Highlights • We designed and synthesized tacrine platinum(II) complexes Pt1 Pt7 as telomerase inhibitors and p53 activators. • Pt5 display high in vivo and in vitro anticancer activity. • Pt5 may trigger cell apoptosis via a mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

Two metal complexes of NiLCl 2 ( 1 ) and [PtLCl]Cl ( 2 ) with 4-([2,2′:6′,2″-terpyridin]-4′-yl)-N,N-diethylaniline ( L ) were synthesized and characterized. 1 and 2 exhibited selective cytotoxicity to T-24 cells more than L , compared with the normal liver cell line (HL-7702). Various experiments showed that L , 1 and 2 caused T-24 cell cycle arrest at S phase, as shown by the down-regulation of cdc25 A, cyclin A, cyclin B and CDK2 and the up-regulation of p21, p27 and p53. Furthermore, complexes 1 and 2 , especially complex 2 , acted as telomerase inhibitors targeting c-myc G-quadruplex DNA and triggered cell apoptosis. In addition, 1 and 2 also caused mitochondrial dysfunction. Taken together, we found that 1 and 2 exerted their cytotoxic activity mainly via inhibiting telomerase by interaction with c-myc quadruplex and disruption of mitochondrial function. [ABSTRACT FROM AUTHOR]

A new platinum(II) complex of [Pt II (L) (pn)]Cl·2H 2 O ( 1 ) (pn = 1,3-propanediamine) with 2-(4-methoxy-phenyl)imidazo [4,5-f]-[1,10]phenanthrolin (H-L) was synthesized and characterized. In complex 1 , the platinum adopts a four-coordinated square planar geometry. Complex 1 exhibited selective cytotoxicity against NCI–H460, BEL-7402, SK-OV-3, SK-OV-3/DDP and HeLa cell lines with IC 50 values in the micromolar range (9.7–35.8 μM), but low cytotoxicity toward normal human liver HL-7702 cells. Complex 1 caused HeLa cell cycle arrest at S phase and it induced HeLa apoptosis by the activation of caspase-3/9. Various experiments showed that complex 1 preferred to bind with G-quadruplex in c-myc. Taken together, we found that complex 1 exerted its antitumor activity mainly via inhibiting telomerase by interaction with c-myc quadruplex and activation of caspase-3/9. [ABSTRACT FROM AUTHOR]

Three platinum(II) complexes, including 2-(2-methoxy-phenyl) imidazo [4,5-f]-[1,10] phenanthroline, 2-(3-methoxy-phenyl) imidazo [4,5-f]-[1,10] phenanthroline and 2-(4-methoxy-phenyl) imidazo [4,5-f]-[1,10] phenanthroline, were synthesised and structurally characterised. In complexes 1-3, the platinum centre adopts a four-coordinate square planar geometry. In the MTT assay, these complexes exhibited considerable cytotoxicities against the SPC-A-2, MGC80-3, BEL-7404 and HeLa human tumour cell lines, with IC50 values in the range of 4.7±0.8 to 23.3±0.4μM, and lower cytotoxicities towards the HL-7702 human normal liver cell line. By flow cytometry analyses, the HeLa cells treated with complexes 1-3 for 72h exhibited DNA damage at the sub-G1 phase with a dose-dependent effect resulting in the blockage of cell cycle at sub-G1 phase, which might contribute to the cell apoptosis observed in HeLa cells. From the results of the CD, UV-vis and FID spectral analyses, complexes 1-3 showed good binding affinity with human telomeric G-quadruplex DNA. It suggested the potential inhibition on the telomerase activity, which should be a key antitumour mechanism for complexes 1-3. Furthermore, complex 1 with 2-substituted MOIP ligand, which may have lower steric hindrance for DNA intercalation, showed higher G-quadruplex DNA binding affinity than complexes 2 and 3. This was supported by the results from cell growth inhibition and cell apoptosis induction. [ABSTRACT FROM AUTHOR]

Abstract: Three mononuclear silver(I) complexes with 8-hydroxyquinoline, 8-hydroxy-2-methylquinoline and 5-chloro-8-quinolinol were synthesized and characterized by elemental analysis, NMR, ESI-MS as well as single crystal X-ray diffraction analysis. All the structures of complexes 1–3 with the silver center adopting an approximately four-coordinated distorted tetragonal pyramid geometry were found to exhibit selective cytotoxicity against HepG2, NCI-H460, BEL-7404 and HeLa cell lines with IC50 values generally in the micromolar range (1.7–14.6μM), but low cytotoxicity towards normal human liver cell HL-7702. A combination of flow cytometric analysis and molecular probe observation indicated that complexes 1–3 could induce HepG2 cell apoptosis. Molecular mechanism studies suggested that complexes 1–3-induced apoptosis is mediated through the intrinsic apoptotic pathway with changes in mitochondrial membrane potential by finally activating effector caspase-3/9 to trigger cell apoptosis. Further studies revealed that complexes 1 and 2 caused cell cycle arrest at S phase, while complex 3 induced G1 cell cycle arrest in HepG2 cells. Taken together, these results suggest that complexes 1–3 may be potential candidates for cancer therapy. [Copyright &y& Elsevier]