One Luminescent Cadmium Iodide with Free Bifunctional Azole Sites as a Triple Sensor for Cu2+, Fe3+, and Cr2O72- Ions.

The exploration of an excellent triple sensor for monitoring Cu2+, Fe3+, and Cr2O72- ions is of exceeding significance because of their serious effects on the human body. Herein, optically active 1H-3,5-bis(pyrazinyl)-1,2,4-triazole (Hbpt) with triazolyl and pyrazinyl groups was applied for the construction of a new type of organic hybrid cadmium iodide [Cd6I8(bpt)4(H2O)4]·2H2O (1) incorporating a hitherto-unknown [Cd3I4(H2O)2]2+ trimeric-cationic unit, which shows an orange light emission at 589 nm with a large Stokes shift of 246 nm. In virtue of the existence of free bifunctional azole sites as the receptors, 1 exhibits a highly selective and sensitive sensing property toward Cu2+, Fe3+, and Cr2O72- ions in aqueous solution with lower detection limits of 0.70∼4.46 ppm, which offers the sole example of cadmium iodide as an excellent triple sensor for detecting Cu2+, Fe3+, and Cr2O72- ions. Moreover, temperature-dependent luminescent determinations also reveal that 1 can be used as the potential luminescent molecular thermometer.

An Electrochemical Sensor Based on Electropolymerization of ß-Cyclodextrin on Glassy Carbon Electrode for the Determination of Fenitrothion.

An electrochemical sensor enabled by electropolymerization (EP) of ß-cyclodextrin on glassy carbon electrode (ß-CDP/GCE) is built for the determination of fenitrothion (FNT). The effects of the EP cycles, pH value, and enrichment time on the electrochemical response of FNT were studied. With the optimum conditions, good linear relationships between the current of the reduction peak of the nitroso derivative of FNT and the concentration are obtained in the range of 10-150 and 150-4000 ng/mL, with a detection limit of 6 ng/mL (S/N = 3). ß-CDP/GCE also exhibits a satisfactory applicability in cabbage and tap water, with recovery values between 98.43% and 112%. These outstanding results suggest that ß-CDP/GCE could be a new effective alternative for the determination of FNT in real samples.

Mitochondria-localizing curcumin-cryptolepine Zn(II) complexes and their antitumor activity.

Many metal complexes are potent candidates as mitochondrial-targeting agents. In this study, four novel Zn(II) complexes, [Zn(BPQA)Cl2] (Zn1), [Zn(BPQA)(Curc)]Cl (Zn2), [Zn(PQA)Cl2] (Zn3), and [Zn(PQA)(Curc)]Cl (Zn4), containing N,N-bis(pyridin-2-ylmethyl)benzofuro[3,2-b]quinolin-11-amine (BPQA), N-(pyridin-2-ylmethyl)benzofuro[3,2-b]quinolin-11-amine (PQA), and curcumin (H-Curc) were synthesized. An MTT assay showed that Zn1-Zn4 had strong anticancer activities against SK-OV-3/DDP and T-24 tumor cells with IC50 values of 0.03-6.19 µM. Importantly, Zn1 and Zn2 displayed low toxicities against normal HL-7702 cells. Mechanism experiments demonstrated that probe Zn2 showed appreciable fluorescence in the red region of the spectrum, and substantial accumulation of Zn2 occurred in the mitochondria after treatment, indicating increases in Ca2+ and reactive oxygen species levels, loss of the mitochondrial membrane potential, and consequent induction of mitochondrial dysfunction at low concentrations. In addition, the probe Zn2 effectively (50.7%) inhibited the growth of T-24 bladder tumor cells in vivo. The probe Zn2 shows potential for use in cancer therapy while retaining the H-Curc as an imaging probe.

Synthesis, Characterization, and Cytotoxicity of the Cobalt (III) Complex with N,N-Diethyl-4-(2,2':6',2''-terpyridin-4'-yl)aniline.

A cobalt(III) complex, [Co(L)2 ](ClO4 )3 (1), in which the ligand L was N,N-diethyl-4-(2,2':6',2''-terpyridin-4'-yl)aniline (L), was synthesized and fully characterized. This new cobalt(III) complex 1 exhibited selective cytotoxicity against HeLa, T-24, A549, MGC80-3, HepG2, and SK-OV-3 cells with IC50 values in the micromolar range (0.52 - 4.33 µm), and it exhibited low cytotoxicity against normal HL-7702 cells. The complex 1 was the most potent against the T-24 cells. It was found that 1 could cause the cell cycle arrest in G1 phase, and it exerted its antitumor activity mainly via disruption of mitochondrial function.

Syntheses, Crystal Structures, and Antitumor Activities of Copper(II) and Nickel(II) Complexes with 2-((2-(Pyridin-2-yl)hydrazono)methyl)quinolin-8-ol.

Two transition metal complexes with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (L), [Cu(L)Cl2]2 (1) and [Ni(L)Cl2]·CH2Cl2 (2), were synthesized and fully characterized. Complex 1 exhibited high in vitro antitumor activity against SK-OV-3, MGC80-3 and HeLa cells with IC50 values of 3.69 ± 0.16, 2.60 ± 0.17, and 3.62 ± 0.12 µM, respectively. In addition, complex 1 caused cell arrest in the S phase, which led to the down-regulation of Cdc25 A, Cyclin B, Cyclin A, and CDK2, and the up-regulation of p27, p21, and p53 proteins in MGC80-3 cells. Complex 1 induced MGC80-3 cell apoptosis via a mitochondrial dysfunction pathway, as shown by the significantly decreased level of bcl-2 protein and the loss of Δψ, as well as increased levels of reactive oxygen species (ROS), intracellular Ca2+, cytochrome C, apaf-1, caspase-3, and caspase-9 proteins in MGC80-3 cells.

Synthesis, Structure Characterization and Antitumor Activity Study of a New Iron(III) Complex of 5-Nitro-8-hydroxylquinoline (HNOQ).

A new iron(III) complex (1) of 5-nitro-8-hydroxylquinoline (HNOQ) was synthesized and structurally characterized in its solid state and solution state by IR, UV-Vis, electrospray ionization (ESI)-MS, elemental analysis, conductivity and X-ray single crystal diffraction analysis. The DNA binding study suggested that complex 1 interacted with calf thymus (ct)-DNA mainly via an intercalative binding mode. By 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the in vitro cytotoxicity of complex 1, comparing with HNOQ and cisplatin, was screened towards a series of tumor cell lines as well as the normal liver cell line HL-7702. Complex 1 showed higher cytotoxicity towards the tested tumor cell lines but lower cytotoxicity towards HL-7702 than HNOQ, in which the T-24 was the most sensitive cell line for 1. Complex 1 caused G2 phase cell cycle arrest and induced cell apoptosis in T-24 cells in a dose-dependent mode, evidenced by changes in cell morphology. Targeting the mitochondrial pathway due to the redox potential of Fe(III)/Fe(II), the apoptotic mechanism in T-24 cells treated by 1 was investigated by reactive oxygen species (ROS) detection, intracellular [Ca(2+)] measurement and caspase-9 and caspase-3 activity assay. It suggested that complex 1 induced cell apoptosis by triggering the caspase-9 and caspase-3 activation via a mitochondrion-mediated pathway.

Oxoisoaporphine as Potent Telomerase Inhibitor.

Two compounds previously isolated from traditional Chinese medicine, Menispermum dauricum (DC), 6-hydroxyl-oxoisoaporphine (H-La), and 4,6-di(2-pyridinyl)benzo[h]isoindolo[4,5,6-de]quinolin-8(5H)-one (H-Lb), were known to have in vitro antitumor activity and to selectively bind human telomeric, c-myc, and bcl-2 G-quadruplexes (G4s). In this study, the binding properties of these two compounds to telomerase were investigated through molecular docking and telomeric repeat amplication protocol and silver staining assay (TRAP-silver staining assay). The binding energies bound to human telomerase RNA were calculated by molecular docking to be -6.43 and -9.76 kcal/mol for H-La and H-Lb, respectively. Compared with H-La, the ligand H-Lb more strongly inhibited telomerase activity in the SK-OV-3 cells model.

A planar Schiff base platinum(II) complex: crystal structure, cytotoxicity and interaction with DNA.

A new platinum(II) complex of salphen derivative, namely Schiff base ligand that derived from o-phenylenediamine and 5-chlorosalicylaldehyde was synthesized. The complex possessed a planar mononuclear structure. The in vitro cytotoxicities of the complex were evaluated by microculture tetrozolium (MTT) assay against seven human tumor cell lines with the IC50 values of ca. 11.61 µM. Cell cycle analysis indicated that the complex induced apoptosis and G1-phase arrest in A549 cells. The results of colony formation assay showed that the complex could suppress the proliferation and viability of A549 cells. The binding of the complex to potential target DNA were investigated by fluorescence spectroscopy, viscosity measurements, fluorescence polarization and agarose gel electrophoresis. The results suggest that the most probable binding mode of the complex is intercalation.

Synthesis and anticancer mechanisms of four novel platinum(II) 4'-substituted-2,2':6',2''-terpyridine complexes.

Mitophagy, a selective autophagic process, has emerged as a pathway involved in degrading dysfunctional mitochondria. Herein, new platinum(II)-based chemotherapeutics with mitophagy-targeting properties are proposed. Four novel binuclear anticancer Pt(II) complexes with 4'-substituted-2,2':6',2''-terpyridine derivatives (tpy1-tpy4), i.e., [Pt2(tpy1)(DMSO)2Cl4]·CH3OH (tpy1Pt), [Pt(tpy2)Cl][Pt(DMSO)Cl3]·CH3COCH3 (tpy2Pt), [Pt(tpy3)Cl][Pt(DMSO)Cl3] (tpy3Pt), and [Pt(tpy4)Cl]Cl·CH3OH (tpy4Pt), were designed and prepared. Moreover, their potential antitumor mechanism was studied. Tpy1Pt-tpy4Pt exhibited more selective cytotoxicity against cisplatin-resistant SK-OV-3/DDP (SKO3cisR) cancer cells compared with those against ovarian SK-OV-3 (SKO3) cancer cells and normal HL-7702 liver (H702) cells. This selective cytotoxicity of Tpy1Pt-tpy4Pt was better than that of its ligands (i.e., tpy1-tpy4), the clinical drug cisplatin, and cis-Pt(DMSO)2Cl2. The results of various experiments indicated that tpy1Pt and tpy2Pt kill SKO3cisR cancer cells via a mitophagy pathway, which involves the disruption of the mitophagy-related protein expression, dissipation of the mitochondrial membrane potential, elevation of the [Ca2+] and reactive oxygen species levels, promotion of mitochondrial DNA damage, and reduction in the adenosine triphosphate and mitochondrial respiratory chain levels. Furthermore, in vivo experiments indicated that the dinuclear anticancer Pt(II) coordination compound (tpy1Pt) has remarkable therapeutic efficiency (ca. 52.4%) and almost no toxicity. Therefore, the new 4'-substituted-2,2':6',2''-terpyridine Pt(II) coordination compound (tpy1Pt) is a potential candidate for next-generation mitophagy-targeting dinuclear Pt(II)-based anticancer drugs.

Anticancer activity of 8-hydroxyquinoline-triphenylphosphine rhodium(III) complexes targeting mitophagy pathways.

Metallodrugs exhibiting distinct mechanisms of action compared with cisplatin hold promise for overcoming cisplatin resistance and improving the efficacy of anticancer drugs. In this study, a new series of rhodium (Rh)(III) complexes containing tris(triphenylphosphine)rhodium(I) chloride [(TPP)3RhCl] (TPP = triphenylphosphine, TPP=O = triphenylphosphine oxide) and 8-hydroxyquinoline derivatives (H-XR1-H-XR4), namely [Rh(XR1)2(TPP)Cl]·(TPP=O) (Yulin Normal University-1a [YNU-1a]), [Rh(XR2)2(TPP)Cl] (YNU-1b), [Rh(XR3)2(TPP)Cl] (YNU-1c), and [Rh(XR4)2(TPP)Cl] (YNU-1d), was synthesized and characterized via X-ray diffraction, mass spectrometry and IR. The cytotoxicity of the compounds YNU-1a-YNU-1d in Hep-G2 and HCC1806 human cancer cell lines and normal HL-7702 cell line was evaluated. YNU-1c exhibited cytotoxicity and selectivity in HCC1806 cells (IC50 = 0.13 ± 0.06 µM, selectivity factor (SF) = 384.6). The compounds YNU-1b and YNU-1c, which were selected for mechanistic studies, induced the activation of apoptotic pathways and mitophagy. In addition, these compounds released cytochrome c, cleaved caspase-3/pro-caspase-3 and downregulated the levels of mitochondrial respiratory chain complexes I/IV (M1 and M4) and ATP. The compound YNU-1c, which was selected for in vivo experiments, exhibited tumor growth inhibition (58.9 %). Importantly, hematoxylin and eosin staining and TUNEL revealed that HCC1806 tumor tissues exhibited significant apoptotic characteristics. YNU-1a-YNU-1d compounds are promising drug candidates that can be used to overcome cisplatin resistance.

8-hydroxyquinoline-N-oxide copper(II)- and zinc(II)-phenanthroline and bipyridine coordination compounds: Design, synthesis, structures, and antitumor evaluation.

Fourteen novel tumor-targeting copper(II) and zinc(II) complexes, [Cu(ONQ)(QD1)(NO3)]·CH3OH (NQ3), [Cu(ONQ)(QD2)(NO3)] (NQ2), [Cu(NQ)(QD2)Cl] (NQ3), [Cu(ONQ)(QD1)Cl] (NQ4), [Cu(ONQ)(QD3)](NO3) (NQ5), [Cu(ONQ)(QD3)Cl] (NQ6), [Zn(ONQ)(QD4)Cl] (NQ7), [Zn(ONQ)(QD1)Cl] (NQ8), [Zn(ONQ)(QD5)Cl] (NQ9), [Zn(ONQ)(QD2)Cl] (NQ10), [Zn(ONQ)(QD6)Cl] (NQ11), [Zn(ONQ)(QD7)Cl] (NQ12), and [Zn(ONQ)(QD3)Cl] (NQ13) supported on 8-hydroxyquinoline-N-oxide (H-ONQ), 2,2'-dipyridyl (QD1), 5,5'-dimethyl-2,2'-bipyridyl (QD2), 1,10-phenanthroline (QD3), 4,4'-dimethoxy-2,2'-bipyridyl (QD4), 4,4'-dimethyl-2,2'-bipyridyl (QD5), 5-chloro-1,10-phenanthroline (QD6), and bathophenanthroline (QD7), were first synthesized and characterized using various spectroscopic techniques. Furthermore, NQ1-NQ13 exhibited higher antiproliferative activity and selectivity for cisplatin-resistant SK-OV-3/DDP tumor cells (CiSK3) compared to normal HL-7702 cells based on results obtained from the cell counting Kit-8 (CCK-8) assay. The complexation of copper(II) ion with QD2 and ONQ ligands resulted in an evident increase in the antiproliferation of NQ1-NQ6, with NQ6 exhibiting the highest antitumor potency against CiSK3 cells compared to NQ1-NQ5, H-ONQ, QD1-QD7, and NQ7-NQ13 as well as the reference cisplatin drug with an IC50 value of 0.17 ± 0.05 µM. Mechanistic studies revealed that NQ4 and NQ6 induced apoptosis of CiSK3 cells via mitophagy pathway regulation and adenosine triphosphate (ATP) depletion. Further, the differential induction of mitophagy decreased in the order of NQ6 > NQ4, which can be attributed to the major impact of the QD3 ligand with a large planar geometry and the Cl leaving group within the NQ6 complex. In summary, these results confirmed that the newly synthesized H-ONQ copper(II) and zinc(II) coordination metal compounds NQ1-NQ13 exhibit potential as anticancer drugs for cisplatin-resistant ovarian CiSK3 cancer treatment.

Platinum(II) 5-substituted-8-hydroxyquinoline coordination compounds induces mitophagy-mediated apoptosis in A549/DDP cancer cells.

For the first time, two new mononuclear platinum(II) coordination compounds, [Pt(L1)(DMSO)Cl] (PtL1) and [Pt(L2)(DMSO)Cl] (PtL2) with the 5-(ethoxymethyl)-8-hydroxyquinoline hydrochloride (H-L1) and 5-bromo-8-hydroxyquinoline (H-L2) have been synthesized and characterized. The cytotoxic activity of PtL1 and PtL2 were screened in both healthy HL-7702 cell line and cancer cell lines, human lung adenocarcinoma A549 cancer cells and cisplatin-resistant lung adenocarcinoma A549/DDP cancer cells (A549R), and were compared to that of the H-L1, H-L2, H-L3 ligands and 8-hydroxyquinoline (H-L3) platinum(II) complex [Pt(L3)(DMSO)Cl] (PtL3). MTT results showed that PtL1 bearing one deprotonated L1 ligand against A549R was more potent by 8.8-48.6 fold than that of PtL2 and PtL3 complexes but was more selective toward healthy HL-7702 cells. In addition, PtL1 and PtL3 overcomes tumour drug resistance by significantly inducing mitophagy and causing the change of the related proteins expression, which leads to cell apoptosis. Moreover, the inhibitory effect of PtL1 on A549 xenograft tumour was 68.2%, which was much higher than that of cisplatin (cisPt, ca. 50.0%), without significantly changing nude mice weight in comparison with the untreated group. This study helps to explore the potential of the platinum(II) 5-substituted-8-hydroxyquinoline coordination compounds for the new Pt-resistant cancer therapy.

Synthesis and anticancer mechanisms of zinc(II)-8-hydroxyquinoline complexes with 1,10-phenanthroline ancillary ligands.

Twenty new zinc(II) complexes with 8-hydroxyquinoline (H-Q1-H-Q6) in the presence of 1,10-phenanthroline derivatives (D1-D10) were synthesized and formulated as [Zn(Q1)2(D1)] (DQ1), [Zn(Q2)2(D2)]·CH3OH (DQ2), [Zn(Q1)2(D3)] (DQ3), [Zn(Q1)2(D4)] (DQ4), [Zn(Q3)2(D5)] (DQ5), [Zn(Q3)2(D4)] (DQ6), [Zn(Q4)2(D5)]·CH3OH (DQ7), [Zn(Q4)2(D6)] (DQ8), [Zn(Q4)2(D3)]·CH3OH (DQ9), [Zn(Q4)2(D1)]·H2O (DQ10), [Zn(Q5)2(D4)] (DQ11), [Zn(Q6)2(D6)]·CH3OH (DQ12), [Zn(Q5)2(D2)]·5CH3OH·H2O (DQ13), [Zn(Q5)2(D7)]·CH3OH (DQ14), [Zn(Q5)2(D8)]·CH2Cl2 (DQ15), [Zn(Q5)2(D9)] (DQ16), [Zn(Q5)2(D1)] (DQ17), [Zn(Q5)2(D5)] (DQ18), [Zn(Q5)2(D10)]·CH2Cl2 (DQ19) and [Zn(Q5)2(D3)] (DQ20). They were characterized using multiple techniques. The cytotoxicity of DQ1-DQ20 was screened using human cisplatin-resistant SK-OV-3/DDP ovarian cancer (SK-OV-3CR) cells and normal hepatocyte (HL-7702) cells. Complex DQ6 showed low IC50 values (2.25 ± 0.13 µM) on SK-OV-3CR cells, more than 3.0-8.0 times more cytotoxic than DQ1-DQ5 and DQ7-DQ20 (≥6.78 µM), and even 22.2 times more cytotoxic than the standard cisplatin, the corresponding free H-Q1-H-Q6 and D1-D10 alone (>50 µM). As a comparison, DQ1-DQ20 displayed nontoxic rates against healthy HL-7702 cells. Furthermore, DQ6 and DQ11 induced significant apoptosis via mitophagy pathways. DQ6 also significantly inhibited tumor growth in an in vivo SK-OV-3-xenograft model (ca. 49.7%). Thus, DQ6 may serve as a lead complex for the discovery of new antitumor agents.

Nanoporous {Y2}-Organic Frameworks for Excellent Catalytic Performance on the Cycloaddition Reaction of Epoxides with CO2 and Deacetalization-Knoevenagel Condensation.

Stable metal-organic frameworks containing periodically arranged nanosized pores and active Lewis acid-base active sites are considered as ideal candidates for efficient heterogeneous catalysis. Herein, the exquisite combination of [Y2(CO2)7(H2O)2] cluster (abbreviated as {Y2}) and multifunctional linker of 2,4,6-tri(2,4-dicarboxyphenyl)pyridine (H6TDP) led to a nanoporous framework of {[Y2(TDP)(H2O)2]·5H2O·4DMF}n (NUC-53, NUC = North University of China), which is a rarely reported binuclear three-dimensional (3D) framework with hierarchical tetragonal-microporous (0.78 nm) and octagonal-nanoporous (1.75 nm) channels. The inner walls of these channels are aligned by {Y2} clusters and plentifully coexisted Lewis acid-base sites of YIII ions and Npyridine atoms. Furthermore, NUC-53 has a quite large void volume of ∼65.2%, which is significantly higher than most documented 3D rare-earth-based MOFs. The performed catalytic experiments exhibited that activated NUC-53 showed a high catalytic activity on the cycloaddition reactions of CO2 with styrene oxide under mild conditions with excellent turnover number (TON: 1980) and turnover frequency (TOF: 495 h-1). Moreover, the deacetalization-Knoevenagel condensation reactions of benzaldehyde dimethyl acetal and malononitrile could be efficiently prompted by the heterogeneous catalyst of NUC-53. These findings not only pave the way for the construction of nanoporous MOF based on rare-earth clusters with a variety of catalytic activities but also provide some new insights into the catalytic mechanism.

Novel bifluorescent Zn(II)-cryptolepine-cyclen complexes trigger apoptosis induced by nuclear and mitochondrial DNA damage in cisplatin-resistant lung tumor cells.

Four novel bifluorescent Zn(II)-cryptolepine-cyclen complexes, namely [Zn(BQTC)]Cl2 (Zn(BQTC)), [Zn(BQA) (Cur)Cl] (Zn(BQACur)), [Zn (TC)]Cl2 (Zn(TC)), and [Zn (AP) (Cur)Cl] (Zn(APCur)), bearing curcumin (H-Cur), cyclen (TC), 1,10-phenanthrolin-5-amine (AP), and novel cryptolepine-cyclen derivatives (BQTC and BQA) were prepared for cell nucleus- and mitochondria-specific imaging. MTT assay results indicated that Zn(BQTC) and Zn(BQACur) exhibit stronger anticancer activity against cisplatin-resistant A549R lung tumor cells than ZnCl2, Zn(TC), Zn(APCur), H-Cur, TC, AP, BQTC, and BQA. Due to the dual fluorescence characteristic of Zn(BQTC), selective fluorescence imaging of the nucleus and mitochondria of A549R cancer cells was conducted. Further, Zn(BQTC), obtained by the functionalization of Zn(TC) with cryptolepine derivative substituents, efficiently inhibited DNA synthesis, thus resulting in high cytotoxicity (selective for A549R lung tumor cells) accompanied by DNA impairment in nuclear and mitochondrial fractions. Additionally, Zn(BQTC) caused severe damage to the mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), sequentially disrupted mitochondrial and nuclear functions, and promoted the DNA damage-induced apoptotic signaling pathway and adenosine triphosphate depletion (ATP). Thus, Zn(BQTC) can be used as an anticancer drug by targeting mtDNA and nDNA. Most importantly, Zn(BQTC) showed higher efficacy in inhibiting cancer growth (55.9%) in A549R tumor-bearing mice than Zn(TC) (31.2%) and cisplatin, along with a promising in vivo safety profile. These results demonstrate the applicability of the developed novel bifluorescent Zn(II)-cryptolepine-cyclen complexes as promising DNA-targeting anticancer agents for cancer treatment.

Complexes of Zn(II) with a mixed tryptanthrin derivative and curcumin chelating ligands as new promising anticancer agents.

In this study, two novel curcumin (H-Cur)-tryptanthrin metal compounds-[Zn(TA)Cl2], i.e., Zn(TA), and [Zn(TA)(Cur)]Cl, i.e., Zn(TAC)-were synthesized and investigated using 5-(bis-pyridin-2-ylmethyl-amino)-pentanoic acid (6,12-dioxo-6,12-dihydro-indolo[2,1-b]quinazolin-8-yl)-amide (TA) and H-Cur as the targeting and high-activity anticancer chemotherapeutic moieties, respectively. They were then compared with the di-(2-picolyl)amine (PA) Zn(II) complex [Zn(PA)Cl2], i.e., Zn(PA). When compared with Zn(PA) and cisplatin, the IC50 values of Zn(TA) and Zn(TAC) indicated that the compounds had high cytotoxicity against A549/DDP cancer cells, implying that the H-Cur-tryptanthrin Zn(II) compounds have the potential for use as anticancer drugs. We propose the use of synthesized theragnostic H-Cur-tryptanthrin Zn(II) complexes with nuclear-targeting and DNA-damaging capabilities as a simple therapeutic strategy against tumors. The Zn(TA) and Zn(TAC) complexes could be traced via red fluorescence and were found to accumulate in the cell nuclei and induce DNA damage, cell cycle arrest, mitochondrial dysfunction, and cell apoptosis both in vitro and in vivo. In addition, Zn(TAC) exhibited a higher antiproliferative effect on A549/DDP than Zn(TA) and Zn(PA), which was undoubtedly associated with the key roles of the novel tryptanthrin derivative TA and H-Cur in the Zn(TAC) complex.

Cell nucleus localization and high anticancer activity of quinoline-benzopyran rhodium(III) metal complexes as therapeutic and fluorescence imaging agents.

Four novel rhodium(III) complexes, [RhIII(QB1)Cl3(DMSO)] (RhN1), [RhIII(QB2)Cl3(CH3OH)]·CH3OH (RhN2), [RhIII(QB3)Cl3(CH3OH)]·CH3OH (RhS), and [RhIII(QB4)Cl3(DMSO)] (RhQ), bearing quinoline-benzopyran ligands (QB1-QB4) were synthesized and used to develop highly anticancer therapeutic and fluorescence imaging agents. Compared with the QB1-QB4 ligands (IC50 > 89.2 ± 1.7 µM for A549/DDP), RhN1, RhN2, RhS and RhQ exhibit selective cytotoxicity against lung carcinoma cisplatin-resistant A549/DDP (A549CDDP) cancer cells, with IC50 values in the range of 0.08-2.7 µM. The fluorescent imaging agent RhQ with the more extended planar QB4 ligand exhibited high anticancer activity in A549CDDP cells and was found in the cell nucleus fraction, whereas RhS had no fluorescence properties. RhQ and RhS may trigger cell apoptosis by causing DNA damage and initiating the mitochondrial dysfunction pathway. Furthermore, RhQ has a higher antitumor efficacy (ca. 55.3%) than RhS (46.4%) and cisplatin (CDDP, 33.1%), and RhQ demonstrated significantly lower toxicity in vivo than CDDP, making it a promising Rh(III)-based anticancer therapeutic and fluorescence imaging agent.

Novel glycosylation zinc(II)-cryptolepine complexes perturb mitophagy pathways and trigger cancer cell apoptosis and autophagy in SK-OV-3/DDP cells.

With the aim of shedding some light on the mechanism of action of zinc(II) complexes in antiproliferative processes and molecular signaling pathways, three novel glycosylated zinc(II)-cryptolepine complexes, i.e., [Zn(QA1)Cl2] (Zn(QA1)), [Zn(QA2)Cl2] (Zn(QA2)), and [Zn(QA3)Cl2] (Zn(QA3)), were prepared by conjugating a glucose moiety with cryptolepine, followed by complexation of the resulting glycosylated cryptolepine compounds N-((1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)methyl)-benzofuro[3,2-b]quinolin-11-amine (QA1), 2-(4-((benzofuro[3,2-b]quinolin-11-ylamino)methyl)-1H-1,2,3-triazol-1-yl)ethan-1-ol (QA2), and (2S,3S,4R,5R,6S)-2-(4-((benzofuro[3,2-b]quinolin-11-ylamino)-methyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (QA3) with zinc(II), and their anticancer activity was evaluated. In MTT assays, Zn(QA1)-Zn(QA3) were more active against cisplatin-resistant ovarian SK-OV-3/DDP cancer cells (SK-OV-3cis) than ZnCl2 and the QA1-QA3 ligands, with IC50 values of 1.81 ± 0.50, 2.92 ± 0.32, and 1.01 ± 0.11 µM, respectively. Complexation of glycosylated cryptolepine QA3 with zinc(II) increased the antiproliferative activity of the ligand, suggesting that Zn(QA3) could act as a chaperone to deliver the active ligand intracellularly, in contrast with other cryptolepine metal complexes previously reported. In vivo and in vitro investigations suggested that Zn(QA3) exhibited enhanced anticancer activity with treatment effects comparable to those of the clinical drug cisplatin. Furthermore, Zn(QA1)-Zn(QA3) triggered SK-OV-3cis cell apoptosis through mitophagy pathways in the order Zn(QA1) > Zn(QA1) > Zn(QA2). These results demonstrate the potential of glycosylated zinc(II)-cryptolepine complexes for the development of chemotherapy drugs against cisplatin-resistant SK-OV-3cis cells.

High anticancer activity and apoptosis- and autophagy-inducing properties of novel lanthanide(III) complexes bearing 8-hydroxyquinoline-N-oxide and 1,10-phenanthroline.

In the quest for rare earth metal complexes with enhanced cancer chemotherapeutic properties, the discovery of seven lanthanide(iii) complexes bearing 8-hydroxyquinoline-N-oxide (NQ) and 1,10-phenanthroline (phen) ligands, i.e., [SmIII(NQ)(phen)(H2O)Cl2] (Ln1), [EuII(NQ)(phen)(H2O)Cl2] (Ln2), [GdIII(NQ)(phen)(H2O)Cl2] (Ln3), [DyIII(NQ)(phen)(H2O)Cl2] (Ln4), [HoIII(NQ)(phen)(H2O)Cl2] (Ln5), [ErIII(NQ)(phen)(H2O)Cl2] (Ln6), and [YbIII(NQ)(phen)(H2O)Cl2] (Ln7), as potential anticancer drugs is described. Complexes Ln1-Ln7 exhibit high antiproliferative activity against cisplatin-resistant A549/DDP cells (IC50 = 0.025-0.097 µM) and low toxicity to normal HL-7702 cells. Moreover, complex Ln1, and to a lesser extent Ln7, can upregulate the expression of LC3 and Beclin1 and downregulate p62 to induce apoptosis in cisplatin-resistant A549/DDP cell lines, which is related to the cell autophagy-inducing properties of Ln1 and Ln7. Furthermore, in vivo assays suggest that Ln1 significantly inhibits A549/DDP xenograft tumor growth (56.5%). These results indicate that lanthanide(iii) complex Ln1 is a promising candidate as an anticancer drug against cisplatin-resistant A549/DDP cells.

Synthesis and biological evaluation of mixed-ligand cyclometalated iridium(III)-quinoline complexes.

With the aim of gaining new insight into the underlying apoptosis mechanisms and in vivo efficacy of cyclometalated Ir(III) complexes as metalodrugs, six new cyclometalated Ir(III)-quinoline complexes, [Ir(1a)(2pq)2] (2a), [Ir(1b)(2pq)2] (2b), [Ir(1c)(2pq)2] (2c), [Ir(1d)(2pq)2] (2d), [Ir(1e)(2pq)2] (2e), and [Ir(1f)(2pq)2] (2f) (2pq = 2-phenylisoquinoline), have been synthesized using 5,7-dihalo-8-hydroxylquinoline ligands (1a-1f) and [Ir(2pq)2Cl]2 precursors and characterized. Complexes 2a-2f have shown potent anticancer activity against cisplatin-resistant SK-OV-3/DDP and A549/DDP cells (IC50 = 0.11-1.83 µM), following the order 2e > 2f > 2b > 2c > 2d > 2a. Confocal microscopy images suggest that 2e and 2b could act as red-color probes for specific cell imaging and efficiently initiate apoptosis and autophagy in the mitochondria, cell cytosol, and nucleus. Overexpression of beclin1, caspase-9, cytochrome c, LC3II, and apaf-1; inhibition of p62, cyclin D1, cyclin A2, and CDK2; and a substantial rapid accumulation suggest a paraptotic mode of cell death induced by autophagy, DNA damage, and mitochondrial stress. In addition, the inhibitory rate of 2e on A549/DDP tumor growth was 64.1% at a concentration of 10.0 mg kg-1, which is clearly higher than that of cisplatin. According to the biological assay, the cyclometalated Ir(III)-quinoline complex 2e exhibited a higher anticancer effect than 2b, which may be associated with the electronic effect of the methyl group of the 1e ligand of 2e playing a key role in the mechanism.