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A facile strategy toward the synthesis of theranostic curcumin–tryptanthrin–Zn(ii) complexes for cancer-specific therapy is demonstrated.

RhQ can be used to target DNA as a highly anticancer therapeutic and fluorescence imaging agent. Importantly, RhQ exhibited significantly more potency than RhS and cisplatin.

Nickel(ii) oxyquinoline–bipyridine complexes inhibit cell growth in A549 and A549/DDP tumor cells via mitophagy pathways.

We herein designed two new PtIV prodrugs of oxoplatin (cis,cis,cis-[PtCl2(NH3)2(OH)2]), [PtIVCl2(NH3)2(O2C-FA)2] (Pt-2) and [PtIVCl2(NH3)2(O2C-RH)2] (Pt-3), by conjugating with ferulic acid (FA-COOH) and rhein (RH-COOH) which have well-known biological activities. Three other Pt(iv) complexes of [PtIVCl2(NH3)2(O2C-BA)2] (Pt-1), [PtIVCl2(NH3)2(O2C-CA)2] (Pt-4) and [PtIVCl2(NH3)2(O2C-TCA)2] (Pt-5) (where BA-COOH = benzoic acid, CA-COOH = crotonic acid and TCA-COOH = trans-cinnamic acid) were also prepared for the comparative study. Like most PtIV prodrug complexes, the cytotoxicity of Pt-3 containing the biologically active rhein (RH-COOH) ligand against lung carcinoma (A549 and A549/DDP) cells was higher than those of Pt-1, Pt-2, Pt-4, cisplatin and Pt-5. Moreover, the cytotoxicity of Pt-3 in HL-7702 normal cells was lower than those of PtIV derivatives bearing BA-COOH, FA-COOH, TCA-COOH and CA-COOH ligands. The highly efficacious Pt-2 and Pt-3 were found to accumulate strongly in the A549/DDP cells, with the prodrug Pt-3 showing highest levels of penetration into the mitochondria. The prodrug Pt-3 effectively entered the A549/DDP cells and caused mitochondrial damage, significantly greater than Pt-2. In addition, the prodrug Pt-3 exhibited higher antitumor efficacy (inhibition rates (IR) = 67.45%) than Pt-2 (28.12%) and cisplatin (33.05%) in the A549/DDP xenograft mouse model. Thus, the prodrug Pt-3 containing the rhein (RH-COOH) ligand is a promising candidate drug targeting the mitochondria.

Four mononuclear cyclometalated iridium(III) complexes, namely, [Ir(FQ)(L1)2] (Ir-1), [Ir(FQ)(L2)2] (Ir-2), [Ir(FQ)(L3)2] (Ir-3) and [Ir(FQ)(L4)2]·2CH3OH (Ir-4) using 5-fluoro-8-quinolinol (H-FQ)-based ligands and [(C^N)2IrCl(μ-Cl)]2 precursor have been first synthesised. The two most effective complexes (containing 7,8-benzoquinoline (H-L3) and 1-phenylpyrazole (H-L4)), Ir-3 and Ir-4, kill HeLa cells in the nanomole range, with the IC50 values of 0.170 ± 0.05 and 0.035 ± 0.002 μM, respectively, indicating that they could potentially inhibit HeLa tumour populations at a lower concentration. Encouragingly, Ir-3 and Ir-4 induce HeLa apoptosis, as indicated by the clear changes in the apoptosis-associated proteins; both accumulate to a high extent in the mitochondrial fraction; promote mitochondrial membrane (MMP) depolarisation and loss of MMP; and trigger caspase-mediated mitochondrial dysfunction apoptosis pathways. To the best of our knowledge, this study is the first to synthesize cyclometalated iridium(III)-5-fluoro-8-quinolinol complexes that can function as mitochondrion-targeting anticancer drugs.

Novel red Zn(ii) complex-based fluorescent probes featuring cryptolepine-curcumin derivatives, namely, [Zn(BQ)Cl2] (BQ-Zn) and [Zn(BQ)(Cur)]Cl (BQCur-Zn), were developed for the simple and fluorescent label-free detection of apoptosis, an important biological process. The probes could synergistically promote mitochondrion-mediated apoptosis and enhance tumor therapeutic effects in vitro and vivo.

Compared with 1–9, 10–13 displayed stronger cytotoxic activities against the tested A549/DDP cells. 11 and 13 could induce apoptosis and autophagy in A549/DDP cells and exhibited pronounced and selective activity against A549/DDP xenografts in vivo.

Two new platinum(II) complexes with naphthalene imide derivatives as the ligands, [Pt(3a)Cl]Cl (3a-Pt) and [Pt(3b)Cl]Cl (3b-Pt), where 3a = 5‑(3‑(bis(pyridin‑2‑ylmethyl)amino)propoxy)‑2‑phenyl‑1H‑benzo[de]isoquinoline‑1,3(2H)‑dione and 3b = 2‑benzyl‑5‑(3‑(bis(pyridin‑2‑ylmethyl)amino)propoxy)‑1H‑benzo[de]isoquinoline‑1,3(2H)‑dione, were synthesized and structurally characterized. 3b-Pt showed higher anti-tumor properties in vitro against human non-small cell lung cancer NCI-H460 cells (0.89 ± 0.25 μM) than 3a-Pt (11.32 ± 0.47 μM) and cisplatin (11.09 ± 1.01 μM). In addition, 3b-Pt induced NCI-H460 cell apoptosis through inhibition of the telomerase activity and dysfunction of mitochondria.

Herein, we report the design and synthesis of three novel binuclear platinum(II) complexes, [Pt(tpbtpy)Cl][Pt(DMSO)Cl3] (tpbtpy-Pt), [Pt(dthbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (dthbtpy-Pt), and [Pt(qlbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (qlbtpy-Pt) with 4′-(3-thiophenecarboxaldehyde)-2,2′:6′,2″-terpyridine (tpbtpy), 4′-(3,5-bis (1,1-dimethylethyl)-2-hydroxy-benzaldehyde)-2,2′:6′,2″-terpyridine (dthbtpy) and 4′-(2-quinolinecarboxaldehyde)-2,2′:6′,2″-terpyridine (qlbtpy) as ligands, respectively. All three novel binuclear platinum(II) complexes tpbtpy-Pt, dthbtpy-Pt, and qlbtpy-Pt were characterized by single-crystal X-ray diffraction analysis, spectroscopic analysis (ESI-MS, IR, 1H NMR), and elemental analysis. Additionally, the cytotoxicity of tpbtpy-Pt, dthbtpy-Pt and qlbtpy-Pt was assessed with human non-small cell lung cancer cell line (NCI H460 cells), yielding IC50 values in the range of 0.35–12.09 μM with tpbtpy-Pt as the most potent and qlbtpy-Pt as the least potent complexes. Mechanistic studies indicated that tpbtpy-Pt and dthbtpy-Pt induced apoptosis through mitochondrial dysfunction and telomerase inhibition. In a NCI H460 xenograft model, when administered at 10.0 mg kg−1 every 2 days, tpbtpy-Pt was shown to significantly reduce tumor growth (tumor growth inhibition rate (IR) = 70.1%, p

Five novel lanthanides(iii) complexes, [Lu(Me)(MBrQ)2NO3] (MeMBrQ-Lu), [Ho(MeO)(MBrQ)2NO3] (MeOMBrQ-Ho), [Ho(Me)(MBrQ)2NO3] (MeMBrQ-Ho), [La(Me)2(BrQ)2NO3] (MeBrQ-La) and [Sm(Me)(BrQ)2(CH3OH)NO3] (MeBrQ-Sm), have been synthesized, in which 2,2′-bipyridyl (4,4′-dimethyl-2,2′-bipyridyl (Me) and 4,4′-dimethoxy-2,2′-bipyridine (MeO)) and 5,7-dibromo-8-quinolinoline derivatives (5,7-dibromo-2-methyl-8-quinolinol (MBrQ-H) and 5,7-dibromo-8-quinolinol (BrQ-H)) act as the chelating ligands. The in vitro cytotoxic activities of the five Ln(iii) complexes have been studied with the SK-OV-3/DDP, NCI-H460 and HeLa cancer cells. MeMBrQ-Lu, MeOMBrQ-Ho, MeMBrQ-Ho, MeBrQ-La and MeBrQ-Sm show higher cytotoxicity against the HeLa cells (IC50 values of 1.00 nM–3.45 μM) than cisplatin (13.11 ± 0.53 μM). In particular, the MeOMBrQ-Ho and MeMBrQ-Ho complexes exhibit superior cytotoxic activity, with IC50 values at 1.00 ± 0.34 nM and 125.00 ± 1.08 nM. We further demonstrate that MeOMBrQ-Ho and MeMBrQ-Ho inhibit the proliferation of HeLa cells by inhibiting telomerase and targeting mitochondria to induce DNA damage-mediated apoptosis. In addition, MeOMBrQ-Ho significantly inhibits tumor growth with a tumor growth inhibition rate (IR) of 50.8% in a HeLa mouse xenograft model. Taken together, MeOMBrQ-Ho is a novel lanthanide(iii) complex with promising antitumor activity.

Two rhodium(III) and iron(III) complexes of 4′-(3-thiophenecarboxaldehyde)-2,2′:6′,2″-terpyridine (tpatpy): [Rh(tpatpy)Cl3]·CH3OH (tpatpy-Rh) and [Fe(tpatpy)Cl3] (tpatpy-Fe) have been prepared and characterized. Tpatpy-Rh (5.03 ± 1.15 μM) and tpatpy-Fe (18.02 ± 0.45 μM) exhibited greater cytotoxicity than the tpatpy ligand (70.11 ± 0.28 μM) and cisplatin (61.21 ± 1.39 μM) against SK-OV-3/DDP cells. In addition, tpatpy-Rh inhibited telomerase by down-regulation of c-myc and hTERT, as well as induced SK-OV-3/DDP cell arrest in the S phase.

In the present study, one novel Pt(II) complex, [Pt(CTD)(DMSO)Cl2] (1) with 9‑chloro‑5,6,7,8‑tetrahydroacridine (CTD) as ligand, was synthesized and fully characterized. The CTD Pt(II) complex 1 was an anti-cancer drug candidate, and it possessed potent therapeutic efficacy for hepatocellular carcinoma (HCC). To explore its mechanism against HCC, Hep‑G2 cells were treated with the CTD Pt(II) complex 1 in vitro. MTT assay showed that the CTD Pt(II) complex 1 had inhibitory activity against five human cancer cells, such as SK‑OV‑3, Hep‑G2, NCI‑H460, MGC80‑3 and HL‑7702, and it displayed the strongest inhibitory activity against Hep‑G2 cells with an IC50 value of 10.48 ± 0.83 μM. Moreover, the CTD Pt(II) complex 1 also exhibited selective cytotoxicity toward the cancer cells. In addition, the CTD Pt(II) complex 1 had low toxicity against non-cancerous HL‑7702 cells. The CTD Pt(II) complex 1 caused mitochondrial dysfunction, leading to the down-regulation of bcl‑2 protein and up-regulation of some mitochondria-initiated apoptotic proteins (including apaf‑1, cytochrome c and bax) in Hep‑G2 cells. Taken together, the CTD Pt(II) complex 1-triggered Hep‑G2 cell apoptosis was mainly mediated via interaction with c‑myc promoter and disruption of mitochondrial pathway. Collectively, our findings supported that the CTD Pt(II) complex 1 could be used as a potential drug candidate for chemoprevention or chemotherapy of HCC.

Four new Pt(II) complexes, [Pt(La)]Cl (1), [Pt(Lb)]Cl (2), [Pt(Lc)]Cl (3) and [Pt(Ld)]Cl (4) with the naphthalene imide derivatives La–Ld as ligands were designed and prepared. MTT assay indicated that 1–4 exhibited proliferation inhibiting activity against human non-small cell lung cancer (NCI-H460) cells, especially 1–3 showed superior activity (IC50 = 0.10–8.56 μM) compared with cisplatin (IC50 = 12.01 ± 1.03 μM). Various experiments showed that 3 as a telomerase inhibitor induced NCI-H460 cell apoptosis via inhibition of the telomerase and dysfunction of mitochondria. In vivo evaluation results suggested that 3 could significantly inhibit the growth of tumor cells in NCI-H460 tumor-bearing mice and the tumor growth inhibition rate (TGI) reached 40.7%. These results demonstrated that 3 is a telomerase inhibitor and a promising anti-cancer agent.

Four novel bifluorescent Zn(II)-cryptolepine-cyclen complexes, namely [Zn(BQTC)]Cl

In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]⋅CH3OH (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 IC50 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 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.

A dinuclear palladium(II) complex, [Pd2(μ‑OAc‑κO,O)2(phpy‑κN,C)2] (1), with 2‑phenylpyridine (H‑phpy) as a ligand was synthesized and characterized by IR, ESI-MS, single-crystal X-ray diffraction, and elemental analysis. By the MTT assay, the dinuclear palladium(II) complex 1 showed lower cytotoxic activity toward normal HL-7702 cells (IC50 = 85.89 ± 0.89 μM). However, it displayed high cytotoxicity against SK-OV-3, NCI-H460, T-24, and HeLa cells, with IC50 values of 5.50 ± 1.08, 0.46 ± 0.28, 7.93 ± 1.16 and 0.35 ± 0.29 μM, respectively. Importantly, we found that this Pd(II) complex exhibited lower toxicity and better anticancer activity than that of cisplatin. Further cellular assays, including Western blotting and flow cytometry, gave evidence that apoptosis after treatment with the dinuclear palladium(II) complex 1 may be induced by the intrinsic mitochondrial dysfunction pathway.

Two novel platinum(ii) complexes, [PtCl2(H-MeOBC)(DMSO)] (Pt1) and [Pt2Cl3(MeOBC)(DMSO)2] (Pt2), with 3-(2'-benzimidazolyl)-8-methoxycoumarin (H-MeOBC) as the ligand were synthesized and evaluated for their antiproliferative activity. Among all the tumor cells, dual-Pt(ii) complex Pt2 exhibited the most potent activity, with an IC50 value of 0.5 ± 0.2 μM against cisplatin-resistant SK-OV-3/DDP cancer cells. In the case of SK-OV-3/DDP cells, Pt2 displayed a 20.1-196.0-fold increased activity when compared with cisplatin, H-MeOBC and Pt1. Importantly, Pt1 and Pt2 displayed low inhibitory rates against normal HL-7702 cells. Further investigation revealed that Pt2 is a novel telomerase inhibitor binding to c-myc promoter elements. Mechanistic studies demonstrated that dual-Pt(ii) complex Pt2 arrests the cell cycle at the G2/M phase and induces apoptosis and causes mitochondrial dysfunction.

Here, two new cyclometallated iridium(III) complexes, [Ir(BrQ)(L1)2] (Ir-1) and [Ir(BrQ)(L2)2] (Ir-2) containing 5-bromo-8-quinolinol (H-BrQ), 2-phenylpyridine (H-L1) and 1-phenylpyrazole (H-L2) ligands have been explored as an anticancer agents targeting mitochondria. The cyclometallated iridium(III) complexes Ir-1 and Ir-2 exhibits excellent antineoplastic activity and promising selectivity towards cervical carcinoma HeLa, with IC50 values were 3.53 ± 0.44 μM and 0.50 ± 0.39 μM, as compared to the human HL-7702 healthy cells and cisplatin-resistant SK-OV-3/DDP cancer cells. Flow cytometry confirmed that cervical carcinoma HeLa cells were caused apoptosis after being treatment with Ir-1 and Ir-2. Along with the decrease of mitochondrial membrane potential (MMP) level, massive release of cytochrome c (cyto C), clear changes in apoptosis-associated proteins, and triggers caspase-mediated mitochondrial dysfunction apoptosis pathways.

To determine the H9C2 cell damage and NLRP3 inflammasome activation trigged by soluble uric acid (UA).H9C2 cells were treated with UA. The cellular damage was examined after 12 h, 24 h and 48 h of treatment using MTS and lactic dehydrogenase (LDH). The apoptosis of H9C2 cells was analyzed by flow cytometry (FCM). NLRP3 inflammasome activation was reflected by the protein levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and Caspase-1 detected by Western blot. The mitochondria and cytoplasm were separated and the release of cytochrome C was detected by Western blot to analyze the damage of mitochondria. The impacts of NAC, a ROS inhibitor, on the cell viability and NLRP3 inflammasome activation were analyzed. The expression of UCP2 was detected by Western blot and immunofluorescence (IF).Dose response and time dependent effects of UA on cellular damage and cell apoptosis was observed. UA up-regulated the expression of NLRP3 inflammasome-related molecules. UA damaged the mitochondria. NAC improved the cell viability and inhibited NLRP3 inflammasome activation. UA down-regulated the expression of UCP2.Soluble UA can down-regulate the expression of UCP2, damage the mitochondria and activate NLRP3 inflammasome, resulting in cellular damage of H9C2 cells.

Two highly active anticancer Pt(II) complexes, [Pt(Jat1)Cl]Cl (Pt1) and [Pt(Jat2)Cl]Cl (Pt2), containing jatrorrhizine derivative ligands (Jat1 and Jat2) are described. Cell intake study showed high accumulation in cell nuclear fraction. Pt1 and Pt2 exhibited high selectivity for HeLa cancer cells (IC50 = 15.01 ± 1.05 nM and 1.00 ± 0.17 nM) comparing with HL-7702 normal cells (IC50 > 150 μM), by targeting p53 and telomerase. Pt2 containing Jat2 ligand was more potent and showed high selectivity for telomerase. It also caused mitochondria and DNA damage, sub-G1 phase arrest, and a high rate of cell apoptosis at the low dose of 1.00 nM. The HeLa tumor inhibition rate (TIR) of Pt2 was 48.8%, which was even higher than cisplatin (35.2%). In addition, Pt2 displayed green luminescent property and potent telomerase inhibition. Our findings demonstrated the promising development of platinum(II) complexes containing jatrorrhizine derivatives as novel Pt-based anti-cancer agents.

A series of novel organoplatinum(II) complexes, [PtII(QC1)(H-QC1)Cl] (Pt1), [PtII(QC2)(H-QC2)Cl] (Pt2), [PtII(QC3)(H-QC3)Cl] (Pt3), [PtII(QC4)(H-QC4)Cl]⋅CH3OH (Pt4), [PtII(QC5)(H-QC5)Cl] (Pt5), [PtII(H-QC6)(DMSO)Cl2] (Pt6), [PtII(H-QC7)(DMSO)Cl2]⋅H2O (Pt7), [PtII(H-QC8)(DMSO)Cl2] (Pt8), [PtII(H-QC9)(DMSO)Cl2]⋅CH3OH (Pt9), [PtII(H-QC10)(DMSO)Cl2] (Pt10) and [PtII(H-QC11)(DMSO)Cl2] (Pt11), bearing quinoline-coumarin derivatives (H-QC1−H-QC11) have been first designed. Complexes Pt1–Pt11 selectively displayed obvious cytotoxicities in comparison to cisplatin for A549/DDP (cisplatin-resistant human lung adenocarcinoma) cells and HeLa cervical carcinoma cells, with IC50 values as low as 100 nM−10.33 μM. In addition, Pt4 and Pt5 display a green-colored luminescent properties, targeted mitochondrial membrane and, thereby induced mainly mitochondria-mediated cell apoptosis was in the following order: Pt4 > Pt5. The different anti-cancer activity of quinoline-coumarin complexes Pt4 (100 nM) and Pt5 (250 nM) were correlate with the presence of 3-(2′-quinolyl)-6-hydroxy-coumarin (H-QC4) ligand. The quinoline-coumarin complex Pt4 (2.0 mg/kg per 2 days) also displayed potent in vivo anti-tumor effect after 21 days-treated. In contrast, the H-QC4 ligand highly enhances the anti-tumor activity and selectivity of organoplatinum(II) complexes in comparison to other previously reported coumarin derivatives metal complexes.

Four platinum(II/IV) complexes, [PtIV(PPy)2Cl2]·CH3OH (Pt1), [PtIV(TFPy)2Cl2] (Pt2), [PtII(MPy)(H-MPy)Cl] (Pt3), and [PtII(DPPy)(H-DPPy)Cl] (Pt4) with 2-phenylpyridine (H-PPy), 2-(4-trifluoromethylphenyl)pyridine (H-TFPy), 3-methyl-2-phenylpyridine (H-MPy) and 2,5-diphenylpyridine (H-DPPy) were first designed and prepared. Cytotoxic properties of Pt1–Pt4 were evaluated in human tumor HeLa (cervical), MCF-7 (breast), Hep-G2 (hepatoma), T-24 (bladder) cells and HL-7702 nontumorigenic cells by means of the MTT assay. The four Pt complexes Pt1–Pt4 were more selective for HeLa (cervical) cells versus normal HL-7702 cells. Remarkably the most active Pt2 compound, having 2-(4-trifluoromethylphenyl)pyridine (H-TFPy) ligand, showed IC50 values down to 1.01 ± 0.34 μM. Importantly, Pt1 and Pt2 induce apoptosis in T-24 (bladder) cells via ROS-mediated mitochondria dysfunction.

Two new quinolone ruthenium(II)-arene complexes, i.e., [Ru(cym)(DClQ)] (Ru1) and [Ru(cym)(ClQ)] (Ru2), with 5,7-dichloro-8-hydroxyquinoline (H-DClQ), 5-chloro-8-hydroxyquinoline (H-ClQ) and [(η6-p-cymene)RuI2]2 (cym), were first designed. The cytotoxic activity of two new quinolone Ru(II)-arene complexes Ru1 and Ru2 has been evaluated in T-24 bladder carcinoma, Hep-G2 hepatoma, BEL-7404 hepatocellular carcinoma, MGC80-3 gastric adenocarcinoma, and non-tumorous HL-7702 liver cells in order to study structure-activity relationships of their anti-tumor activity. Additionally, the cytotoxic activity of quinolone Ru(II)-arene complex Ru1 was much higher potent than Ru2 and cisplatin, with low IC50 values was 0.02 ± 0.0.1 μM against T-24 bladder carcinoma cells. The mechanism studies testified that quinolone Ru(II)-arene complexes Ru1 and Ru2 induced apoptosis in T-24 bladder carcinoma cells by generating ROS metabolites, triggering caspase-9 increase and mitochondrial membrane potential loss. The quinolone Ru(II)-arene complex Ru1 with 5,7-dichloro-8-hydroxyquinoline (H-DClQ) ligand was considerably more active than the 5-chloro-8-hydroxyquinoline Ru2 complex.