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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]

There iridium(III) complexes, [Ir(3-MeO-Phtpy)Cl 3 ] ( 1 ), [Ir(2-MeO-Phtpy)Cl 3 ] ( 2 ) and [Ir(4-MeO-Phtpy)Cl 3 ] ( 3 ) with 4′-(3-methoxyphenyl)-2,2′:6′,2″-terpyridine (3-MeO-Phtpy), 4′-(2-methoxyphenyl)-2,2′:6′,2″-terpyridine (2-MeO-Phtpy) and 4′-(4-methoxyphenyl)-2,2′:6′,2″-terpyridine (4-MeO-Phtpy) as ligands, respectively, were synthesized and evaluated for their antiproliferative activities. In these complexes, the iridium(III) center adopts a six-coordinate distorted octahedral geometry. Among them, complex 1 exhibited the most potent activity, with IC 50 values of 3.19–27.77 μ M against four cancer cell lines (BEL-7404, Hep-G2, NCI-H460 and MGC80-3 cells). Cellular mechanism studies suggested that complexes 1 – 3 directly targeted c-myc promoter elements and inhibited the telomerase activity. In addition, complexes 1 – 3 may trigger cell apoptosis via a mitochondrial dysfunction pathway. We postulated that the difference in the in vitro antitumor activities of complexes 1 – 3 is mainly dependent on the position of the methoxy group on the phenyl ring of the iridium ligand. [ABSTRACT FROM AUTHOR]

Two G-quadruplex ligands: [Co( H-L a ) 2 Cl 2 ] ( Co1 ) and [Co( L b ) 2 ][CoCl 4 ]⋅2H 2 O ( Co2 ) have been synthesized and characterized. Two cobalt oxoisoaporphine complexes exhibited selective cytotoxicity to SK-OV-3/DDP cells than for HL-7702 cells. Cytotoxic mechanism studies indicated that both Co1 and Co2 were telomerase inhibitor targeting c-myc, telomere, and bcl-2 G4s, and triggering cell senescence and apoptosis, which caused S phase arrest. They also induced mitochondrial dysfunction. The better antitumor activity of Co2 , which should be correlated with a moiety of 2-[5-(2-pyridinyl)-1 H -pyrrol-2-yl]pyridine in the L b . Importantly, Co2 at high doses showed at least the same level of tumor growth inhibition efficacy compared to that of cisplatin, and better in vivo safety profile. [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]