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Two new Pt(II) complexes with sorafenib (SRFN) and regorafenib (RGFN), having the general formulae [Pt(SRFN)(DMSO)Cl2] (SRFN-Pt) and [Pt(RGFN)(DMSO)Cl2] (RGFN-Pt), were prepared and characterized by ESI-MS, IR, UV–Vis spectroscopy, elemental analyses, and 1H and 13C NMR, respectively. The anticancer activities of SRFN-Pt and RGFN-Pt were evaluated by MTT assay with NCI-H460 (human non-small cell lung cancer NCI-H460 cell line), SK-OV-3 (ovarian cancer cell line), SK-OV-3/DDP (cisplatin-resistant SK-OV-3 cell line), T-24 (human bladder cancer cell line), HeLa (cervical cancer cell line), A549/DDP (cisplatin-resistant A549/DDP non-small cell lung cancer cell line) cancer cells and in the normal HL-7702 cells. The results suggested that SRFN-Pt and RGFN-Pt were more effective against the A549/DDP tumor cells (IC50 = 1.18 ± 0.15 μM and 0.13 ± 0.03 μM) than SRFN (45.03 ± 0.79 μM), RGFN (40.11 ± 2.15 μM), and cisplatin (97.63 ± 1.06 μM), respectively, and RGFN-Pt was more effective than SRFN-Pt. In addition, SRFN-Pt and RGFN-Pt induced G2/M and S phase arrest. Cytotoxic mechanism studies revealed that SRFN-Pt and RGFN-Pt triggered mitochondria-mediated apoptotic cell death at low concentration. RGFN-Pt exhibited obvious priority on the in vitro antitumor activity than SRFN-Pt, which should be undoubtedly correlated with the key roles of the fluoro substituted groups in the RGFN ligand of RGFN-Pt. The in vitro anti-tumor activity studies suggested that RGFN-Pt pointed to a new direction in developing Pt(II) drugs as anti-cancer agent.

A series of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives (5a1−5d6) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activity against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicity against the HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results demonstrated that 5a3 exhibited effective inhibition on tumor growth in the NCI-H460 xenograft mouse model and that 5d3 displayed excellent antiproliferative activity in the BEL-7402 xenograft model. These results suggested that both 5a3 and 5d3 could be used as anticancer drug candidates. Mechanistic studies suggested that compounds 5a3 and 5d3 exerted their antitumor activity by up-regulation of Bax, intracellular Ca2+ release, ROS generation, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, inhibition of CDK activity and activation of the p53 protein.

Lysicamine is a natural oxoaporphine alkaloid, which isolated from traditional Chinese medicine (TCM) herbs and has been shown to possess cytotoxicity to hepatocarcinoma cell lines. Reports on its antitumor activity are scarce because lysicamine occurs in plants at a low content. In this work, we demonstrate a facile concise total synthesis of lysicamine from simple raw materials under mild reaction conditions, and the preparation of the Ru(II), Rh(III), Mn(II) and Zn(II) complexes 1-4 of lysicamine (LY). All the compounds were fully characterized by elemental analysis, IR, ESI-MS, 1H and 13C NMR, as well as single-crystal X-ray diffraction analysis. Compared with the free ligand LY, complexes 2 and 3 exhibited superior in vitro cytotoxicity against HepG2 and NCI-H460. Mechanistic studies indicated that 2 and 3 blocked the cell cycle in the S phase by decreasing of cyclins A2/B1/D1/E1, CDK 2/6, and PCNA levels and increasing levels of p21, p27, p53 and CDC25A proteins. In addition, 2 and 3 induced cell apoptosis via both the caspase-dependent mitochondrial pathway and the death receptor pathway. in vivo study showed that 2 inhibited HepG2 tumor growth at 1/3 maximum tolerated dose (MTD) and had a better safety profile than cisplatin.

// Qi-Pin Qin 1 , Jiao-Lan Qin 1 , Ming Chen 1 , Yu-Lan Li 1 , Ting Meng 1 , Jie Zhou 1 , Hong Liang 1 and Zhen-Feng Chen 1 1 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, P. R. China Correspondence to: Hong Liang, email: hliang@gxnu.edu.cn Zhen-Feng Chen, email: chenzf@gxnu.edu.cn Keywords: chiral platinum(II) complex, oxoaporphine, G-quadruplex DNA, telomerase, antitumor activity Received: March 01, 2017 Accepted: May 06, 2017 Published: June 28, 2017 ABSTRACT Three platinum(II) complexes, 4 (LC-004), 5 (LC-005), and 6 (LC-006), with the chiral FOA ligands R/S-(±)-FOA (1), R-(+)-FOA (2) and S-(–)-FOA (3), respectively, were synthesized and characterized. As potential anti-tumor agents, these complexes show higher cytotoxicity to BEL-7404 cells than the HL-7702 normal cells. They are potential telomerase inhibitors that target c-myc and human telomeric G-quadruplex DNA. Compared to complexes 4 and 5, 6 exhibited higher binding affinities towards telomeric, c-myc G-quadruplex DNA and caspase-3/9, thereby inducing senescence and apoptosis to a greater extent in tumor cells. Moreover, our in vivo studies showed that complex 6 can effectively inhibit tumor growth in the BEL-7404 and BEL-7402 xenograft mouse models and is less toxic than 5-fluorouracil and cisplatin. The effective inhibition of tumor growth is attributed to its interactions with 53BP1, TRF1, c-myc, TRF2, and hTERT. Thus, complex 6 can serve as a novel lead compound and a potential drug candidate for anticancer chemotherapy.

Platinum-based anticancer drugs have been successfully applied in clinical, which greatly promoted the development of metal-based medicinal chemistry. Currently, seeking for metal-based drugs with new action mechanism has become one of the hot topics in medicinal chemistry. Herein, we review the research progress on antitumor and antibacterial activity of 8-hydroxyquinoline and its derivatives’ metal complexes. From synthesis, structure, activity, action mechanism and structure-activity relationship, the recent progress of 8-hydroxyquinoline and its derivatives’ metal complexes with antitumor activity have been summarized. Also, the advances of 8-hydroxyquinoline and its derivatives’ antibacterial metal complexes have been reviewed. Basing the facts mentioned-above, we find some active groups and some trends of halo-substituted effect, which may afford important references for designing and developing new antitumor and antibacterial 8-hydroxyquinoline and its derivatives’ metal-based drugs.

The reactions of mangiferin (H-MF) with Cu(II) and Zn(II) yielded [Cu(MF)(OH)(H2O)]x5H2O and [Zn(MF)(OH)(H2O)]x4H2O. The MTT assay against four tumour cell lines revealed that the Cu complex generally showed higher in vitro cytotoxicity vs. free H-MF than the Zn complex, which may be due to the different bioactivities of Cu(II) and Zn(II). DNA binding studies of both complexes vs. H-MF indicated that they tended to bind intercalatively with DNA. Both complexes also exhibited topoisomerase I inhibition at 100 μM, which could be due to their DNA binding affinities.

Complexes of yttrium(III) and dysprosium(III) with the traditional Chinese medicine active ingredient oxoglaucine (OG), namely [Y(OG)2(NO3)3]·CH3OH (1) and [Dy(OG)2(NO3)3]·H2O (2), were synthesized and characterized by elemental analysis, IR, ESI-MS, (1)H and (13)C NMR as well as single-crystal X-ray diffraction analysis. In vitro the complexes exhibited higher anticancer activity than the free ligand OG against the tested cancer cell lines. Among the tested cell lines, HepG2 is the most sensitive to the complexes. Complex 2 can trigger DNA damage in HepG2 cells, resulting in cell cycle arrest in the S phase and leading to cell apoptosis. The S phase cell-cycle arrest is caused via the ATM (ataxia-telangiectasia mutated)-Chk2-Cdc25A pathway. Chk2 is phosphorylated and activated in an ATM-dependent manner. It, in turn, phosphorylates Cdc25A phosphatise on serine124, causing the inactivation of Cdc25A in ubiquitin-mediated proteolytic degradation. The cyclin-Cdk complexes of the S phase could also be inhibited by limited supply of cyclins A and E. This irreversible cell cycle arrest process ultimately induces mitochondria-involved apoptotic cell death via the activation of Bcl-2 protein. Complex e2 ffectively inhibited tumour growth in the BEL-7402 xenograft mouse model and exhibited higher safety in vivo than cisplatin.

Lysicamine is a natural oxoaporphine alkaloid, which isolated from traditional Chinese medicine (TCM) herbs and has been shown to possess cytotoxicity to hepatocarcinoma cell lines. Reports on its antitumor activity are scarce because lysicamine occurs in plants at a low content. In this work, we demonstrate a facile concise total synthesis of lysicamine from simple raw materials under mild reaction conditions, and the preparation of the Ru(II), Rh(III), Mn(II) and Zn(II) complexes 1–4 of lysicamine (LY). All the compounds were fully characterized by elemental analysis, IR, ESI-MS, 1H and 13C NMR, as well as single-crystal X-ray diffraction analysis. Compared with the free ligand LY, complexes 2 and 3 exhibited superior in vitro cytotoxicity against HepG2 and NCI-H460. Mechanistic studies indicated that 2 and 3 blocked the cell cycle in the S phase by decreasing of cyclins A2/B1/D1/E1, CDK 2/6, and PCNA levels and increasing levels of p21, p27, p53 and CDC25A proteins. In addition, 2 and 3 induced cell apoptosis via both the caspase-dependent mitochondrial pathway and the death receptor pathway. in vivo study showed that 2 inhibited HepG2 tumor growth at 1/3 maximum tolerated dose (MTD) and had a better safety profile than cisplatin.

Three new oxoaporphine Co(II), Ni(II) and Zn(II) complexes 1–3 have been synthesized and fully characterized. 1–3 have similar mononuclear structures with the metal and ligand ratio of 1:2. 1–3 exhibited higher cytotoxicity than the OD ligand and cisplatin against HepG2, T-24, BEL-7404, MGC80–3 and SK-OV-3/DDP cells, with IC50 value of 0.23−4.31 μM. Interestingly, 0.5 μM 1–3 significantly caused HepG2 arrest at S-phase, which was associated with the up-regulation of p53, p21, p27, Chk1 and Chk2 proteins, and decrease in cyclin A, CDK2, Cdc25A, PCNA proteins. In addition, 1–3 induced HepG2 apoptosis via a caspase-dependent mitochondrion pathway as evidenced by p53 activation, ROS production, Bax up-regulation and Bcl-2 down-regulation, mitochondrial dysfunction, cytochrome c release, caspase activation and PARP cleavage. Furthermore, 3 inhibited tumor growth in HepG2 xenograft model, and displayed more safety profile in vivo than cisplatin.

A series of group-10 metal complexes 1–14 of oxoisoaporphine derivatives were designed and synthesized. 1–14 were more selectively cytotoxic to Hep-G2 cells comparing with normal liver cells. In vitro cytotoxicity results showed that complexes 1–6, 7, 8, 10 and 11, especially 3, were telomerase inhibitors targeting c-myc, telomeric, and bcl-2 G4s and triggered cell senescence and apoptosis; they also caused telomere/DNA damage and S phase arrest. In addition, 1–6 also caused mitochondrial dysfunction. Notably, 3 with 6-amino substituted ligand La exhibited less side effects than 6 with 8-amino substituted ligand Lb and cisplatin, but similar tumor growth inhibition efficacy in BEL-7402 xenograft model. Complex 3 has the potential to be developed as an effective anticancer agent.

Three new oxoaporphine Co(II), Ni(II) and Zn(II) complexes 1–3 have been synthesized and fully characterized. 1–3 have similar mononuclear structures with the metal and ligand ratio of 1:2. 1–3 exhibited higher cytotoxicity than the OD ligand and cisplatin against HepG2, T-24, BEL-7404, MGC80–3 and SK-OV-3/DDP cells, with IC50 value of 0.23−4.31 μM. Interestingly, 0.5 μM 1–3 significantly caused HepG2 arrest at S-phase, which was associated with the up-regulation of p53, p21, p27, Chk1 and Chk2 proteins, and decrease in cyclin A, CDK2, Cdc25A, PCNA proteins. In addition, 1–3 induced HepG2 apoptosis via a caspase-dependent mitochondrion pathway as evidenced by p53 activation, ROS production, Bax up-regulation and Bcl-2 down-regulation, mitochondrial dysfunction, cytochrome c release, caspase activation and PARP cleavage. Furthermore, 3 inhibited tumor growth in HepG2 xenograft model, and displayed more safety profile in vivo than cisplatin.

Two G-quadruplex ligands: [Co(H-La)2Cl2] (Co1) and [Co(Lb)2][CoCl4]⋅2H2O (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)-1H-pyrrol-2-yl]pyridine in the Lb. 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.

[Pd(L)(DMSO)Cl2] (1) and [Pt(L)(DMSO)Cl2] (2) with 9-amino-oxoisoaporphine (L), were synthesized and characterized. 1 and 2 are more selectively cytotoxic to Hep-G2 cells versus normal liver cells (HL-7702). Various experiments showed that 2 acted as telomerase inhibitors targeting G4-DNA and triggered cell apoptosis by interacting with c-myc G4-DNA. Furthermore, 2 significantly induced cell cycle arrest at both G2/M and S phase, which leading to the down-regulation of cdc25 A, cyclin D, cyclin B, cyclin A and CDK2 and the up-regulation of p53, p27, p21,chk1 and chk2. In addition, 2 also caused mitochondrial dysfunction. Taken together, we found that 2 exerted its cytotoxic activity mainly via inhibiting telomerase by interaction with c-myc G4-DNA and disruption of mitochondrial function.

A new anthracycline derivative, anthracene-9-imidazoline hydrazone (9-AIH), was synthesized and selected as an antitumor ligand to afford a copper(II) complex of 9-AIH, cis-[Cu(II)Cl2(9-AIH)] (1). Complex 1 was structurally characterized by IR, elemental analysis, ESI-MS and single crystal X-ray diffraction analysis. By MTT assay, it was revealed that 1 showed overall a higher in vitro cytotoxicity than 9-AIH towards a panel of human tumour cell lines, with IC50 values from 0.94–3.68 μM, in which the BEL-7404 cell line was the most sensitive to 1. By spectral analyses and gel electrophoresis, the DNA binding affinity of 9-AIH and 1 was determined. 9-AIH was suggested to bind with DNA in an intercalative mode, with a quenching constant of 1.04 × 10(4) M(−1) on the EB–DNA complex. While for 1, both intercalative and covalent binding modes were suggested. By flow cytometry, 1 was found to block the cell cycle of BEL-7404 cells in a dose-dependent mode, in which it induced the G2/M phase arrest at 0.5 μM and induced the S phase arrest at higher concentrations of 1.0 or 2.0 μM. From the cellular morphological observations under different fluorescence probe staining, a dose-dependent manner of 1 to induce cell apoptosis in the late stage was suggested. Comparatively, equivalent apoptotic cells, respectively, in the early and late stages were found when incubated with 2.0 μM of 9-AIH. The mitochondrial membrane potential measured by JC-1 staining and the ROS generation in cells detected using a DCFH-DA probe suggested that the cell apoptosis induced by 1 might undergo the ROS-related mitochondrial pathway. Accordingly, the mutant p53 expression was found to be suppressed and the caspase cascade (caspase-9/3) was consequently activated by 1. This action mechanism for 1 in the BEL-7404 cells was unique and was not found in the presence of 9-AIH under the same conditions, indicating their different antitumor mechanism. Furthermore, the in vivo acute toxicity of 1 tested on mice indicated that 1 should be a high cytotoxic antitumor agent, with the LD50 value in the range of 32–45 mg kg(−1), which is much higher than that of 9-AIH. From the above results, the central Cu(II) of 1 in the coordinated mode with 9-AIH was believed to play a key role in exerting both the high cytotoxicity and the effective antitumor mechanism.

Two G-quadruplex ligands [Pt(L(a))(DMSO)Cl] (Pt1) and [Pt(L(b))(DMSO)Cl] (Pt2) have been synthesized and fully characterized. The two complexes are more selective for SK-OV-3/DDP tumor cells versus normal cells (HL-7702). It was found that both Pt1 and Pt2 could be a telomerase inhibitor targeting G-quadruplex DNA. This is the first report demonstrating that telomeric, c-myc, and bcl-2 G-quadruplexes and caspase-3/9 preferred to bind with Pt2 rather than Pt1, which also can induce senescence and apoptosis. The different biological behavior of Pt1 and Pt2 may correlate with the presence of a 6-hydroxyl group in L(b). Importantly, Pt1 and Pt2 exhibited higher safety in vivo and more effective inhibitory effects on tumor growth in the HCT-8 and NCI-H460 xenograft mouse model, compared with cisplatin. Taken together, these mechanistic insights indicate that both Pt1 and Pt2 display low toxicity and could be novel anticancer drug candidates.

[Pt(Q)2] (1) and [Pt(MQ)2] (2) exhibited enhanced cytotoxicity against BEL-7404, Hep-G2, NCI-H460, T-24, A549 tumor cells but low cytotoxicity on normal HL-7702 cells. 1 and 2 could cause the cell cycle arrest in G2 and S phase, respectively. While pifithrin-α, a specific p53 inhibitor, induced cell cycle arrest in G1 phase. Although 1, 2 and pifithrin-α caused serious inhibition on p53, 1 and 2 significantly cause the loss of mitochondrial membrane potential and increase of the reactive oxygen species level, cytochrome c, apaf-1 and caspase-3/9 ratio in BEL-7404 cells. 1 and 2 may trigger the cell apoptosis through a mitochondrial dysfunction pathway whereas pifithrin-α does not. The interactions of 1 and 2 with DNA are most probably via an intercalation.