RESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Diseño de Fármacos , Quinolonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Ciclo Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Quinolonas/síntesis química , Quinolonas/química , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
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.
RESUMEN
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.
RESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Aporfinas/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Metales/farmacología , Mitocondrias/metabolismo , Fase S/efectos de los fármacos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Aporfinas/síntesis química , Aporfinas/química , Calcio/metabolismo , Caspasas/metabolismo , Forma de la Célula/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Citocromos c/metabolismo , Daño del ADN , ADN-Topoisomerasas de Tipo II/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Células Hep G2 , Humanos , Ligandos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Modelos Biológicos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Neoplasias/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Senescencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Daño del ADN/efectos de los fármacos , G-Cuádruplex/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patología , Telómero/efectos de los fármacos , Telómero/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Two G-quadruplex ligands: [Co(H-La)2Cl2] (Co1) and [Co(Lb)2][CoCl4]â 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.
Asunto(s)
Aporfinas/química , Cobalto/química , ADN/metabolismo , G-Cuádruplex/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Compuestos Organometálicos/farmacología , Telomerasa/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Transporte Biológico , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Ciclina A/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , ADN/química , Regulación hacia Abajo/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Mitocondrias/patología , Compuestos Organometálicos/química , Compuestos Organometálicos/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Relación Estructura-Actividad , Telómero/metabolismoRESUMEN
[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.
Asunto(s)
Apoptosis/efectos de los fármacos , ADN/química , G-Cuádruplex/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Compuestos Organometálicos/farmacología , Proteínas Proto-Oncogénicas c-myc/genética , Telomerasa/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Aporfinas/química , Transporte Biológico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , ADN/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/patología , Compuestos Organometálicos/química , Compuestos Organometálicos/metabolismo , Platino (Metal)/química , Especies Reactivas de Oxígeno/metabolismo , Solubilidad , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacosRESUMEN
Three water-soluble ruthenium(II) complexes with chiral 4-(2,3-dihydroxypropyl)-formamide oxoaporphine (FOA) were synthesized and characterized. It was found that these ruthenium(II) complexes exhibited considerable in vitro anticancer activities and that they were the effective stabilizers of telomeric and G-quadruplex-DNA (G4-DNA) in promoter of c-myc, which acted as a telomerase inhibitor targeting G4-DNA and induced cell senescence and apoptosis. Interestingly, the in vitro anticancer activity of 6 (LC-003) was higher than those of 4 (LC-001) and 5 (LC-002), more selective for BEL-7404 cells than for normal HL-7702 cells, and preferred to activate caspases-3/9. The different biological behaviors of the ruthenium complexes could be correlated with the chiral nature of 4-(2,3-dihydroxypropyl)-formamide oxoaporphine. More significantly, 6 exhibited effective inhibitory on tumor growth in BEL-7402 xenograft mouse model and higher in vivo safety than cisplatin. These mechanistic insights indicate that 6 displays low toxicity and can be a novel anticancer drug candidate.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Complejos de Coordinación/farmacología , ADN/química , G-Cuádruplex/efectos de los fármacos , Neoplasias Hepáticas/patología , Compuestos de Rutenio/farmacología , Telomerasa/antagonistas & inhibidores , Animales , Western Blotting , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Compuestos de Rutenio/química , Solubilidad , Relación Estructura-Actividad , Telomerasa/genética , Telomerasa/metabolismo , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Agua/químicaRESUMEN
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.
Asunto(s)
Antineoplásicos , Apomorfina/análogos & derivados , Complejos de Coordinación , Disprosio , Inhibidores de Topoisomerasa , Itrio , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apomorfina/química , Apomorfina/farmacología , Apomorfina/uso terapéutico , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , ADN/metabolismo , Daño del ADN , Disprosio/química , Disprosio/farmacología , Disprosio/uso terapéutico , Humanos , Medicina Tradicional China , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Fase S/efectos de los fármacos , Solubilidad , Inhibidores de Topoisomerasa/química , Inhibidores de Topoisomerasa/farmacología , Inhibidores de Topoisomerasa/uso terapéutico , Carga Tumoral/efectos de los fármacos , Agua/química , Difracción de Rayos X , Itrio/química , Itrio/farmacología , Itrio/uso terapéuticoRESUMEN
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 0.943.68 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 EBDNA 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 3245 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.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Cobre/química , Cobre/farmacología , Hidrazonas/química , Hidrazonas/farmacología , Animales , Antracenos/síntesis química , Antracenos/química , Antracenos/farmacología , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Cristalografía por Rayos X , Femenino , Humanos , Hidrazonas/síntesis química , Imidazolidinas/síntesis química , Imidazolidinas/química , Imidazolidinas/farmacología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Aporfinas/farmacología , ADN/química , Inhibidores Enzimáticos/farmacología , G-Cuádruplex , Neoplasias/patología , Compuestos Organoplatinos/farmacología , Telomerasa/antagonistas & inhibidores , Animales , Antineoplásicos/química , Aporfinas/química , Western Blotting , Ciclo Celular/efectos de los fármacos , Senescencia Celular , Cristalografía por Rayos X , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/química , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias/tratamiento farmacológico , Compuestos Organoplatinos/química , Relación Estructura-ActividadRESUMEN
[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.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Compuestos Organoplatinos/farmacología , Oxiquinolina/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Estructura Molecular , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Relación Estructura-ActividadRESUMEN
The contents of twenty microelements were determined in the root, stem and leaf of traditional Chinese herbs, Zanthoxylum nitidum by ICP-AES (inductively coupled plasma-atomic emission spectrometry) analytical technology. For such method, their recovery ratio obtained by standard addition method ranged between 89% and 107.5%, and most of RSDs were lower than 4%, with good correction and precision. The analytical results show that there exist different contents from the different parts of the plant. There are most rich elements such as Mg, Na, K, and Ca in its three parts, while Mn, Zn, Fe, Cu, Co, Sr and some toxic elements Cd, Cr, Pb and Bi were also detected; four elements, Se, V, Mo and Hg, were not detected in all parts. There exist many kinds of metal elements benefiting human being health, which may provide useful information for the usage of the herbs and for the study of the relationship between the elements in Chinese traditional medicine and its bioactivities.