RESUMEN
The cobalt(II), copper(II) and zinc(II) complexes of 1,10-phenanthroline (phen) and maltol (mal) (complexes 1, 2, 3 respectively) were prepared from their respective metal(II) chlorides and were characterized by FT-IR, elemental analysis, UV spectroscopy, molar conductivity, p-nitrosodimethylaniline assay and mass spectrometry. The X-ray structure of a single crystal of the zinc(II) analogue reveals a square pyramidal structure with distinctly shorter apical chloride bond. All complexes were evaluated for their anticancer property on breast cancer cell lines MCF-7 and MDA-MB-231, and normal cell line MCF-10A, using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and morphological studies. Complex 2 was most potent for 24, 48 and 72 h treatment of cancer cells but it was not selective towards cancer over normal cells. The mechanistic studies of the cobalt(II) complex 1 involved apoptosis assay, cell cycle analysis, dichloro-dihydro-fluorescein diacetate assay, intracellular reactive oxygen species assay and proteasome inhibition assay. Complex 1 induced low apoptosis, generated low level of ROS and did not inhibit proteasome in normal cells. The study of the DNA binding and nucleolytic properties of complexes 1-3 in the absence or presence of H2O2 or sodium ascorbate revealed that only complex 1 was not nucleolytic.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Fenantrolinas/farmacología , Pironas/farmacología , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cobalto/química , Complejos de Coordinación/síntesis química , Cobre/química , ADN/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Fenantrolinas/síntesis química , Inhibidores de Proteasoma/síntesis química , Inhibidores de Proteasoma/farmacología , Pironas/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Zinc/químicaRESUMEN
Phosphanegold(I) thiolates, Ph3PAu[SC(OR)=NPh], R=Me (1), Et (2) and iPr (3), were previously shown to be significantly cytotoxic toward HT-29 cancer cells and to induce cell death by both intrinsic and extrinsic apoptotic pathways whereby 1 activated the p73 gene, and each of 2 and 3 activated p53; 2 also caused apoptotic cell death via the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway. Apoptosis pathways have been further evaluated by mitochondrial cytochrome c measurements and annexin V screening, confirming apoptotic pathways of cell death. Cell cycle analysis showed the majority of treated HT-29 cells were arrested at the G2/M checkpoint after 24h; results of both assays were confirmed by changes in populations of relevant genes (PCR array analysis). Cell invasion studies showed inhibition of metastasis through Matrigel™ matrix to 17-22% cf. untreated cells. LC50 values were determined in zebrafish (8.36, 8.17, and 7.64µM for 1-3). Finally, the zebrafish tolerated doses of 1 and 2 up to 0.625µM, and 3 was tolerated at even higher doses of up to 1.25µM.
Asunto(s)
Citotoxinas , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Compuestos Orgánicos de Oro , Pez Cebra/embriología , Animales , Línea Celular Tumoral , Citotoxinas/síntesis química , Citotoxinas/química , Citotoxinas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Invasividad Neoplásica , Neoplasias/metabolismo , Neoplasias/patología , Compuestos Orgánicos de Oro/síntesis química , Compuestos Orgánicos de Oro/química , Compuestos Orgánicos de Oro/farmacologíaRESUMEN
Four compounds, R3PAu[S2CN(CH2CH2OH)2], R=Ph (1) and cyclohexyl (2), and Et3PAuS2CNRê2, Rê=Rê=Et (3) and Rê2=(CH2)4 (4), have been evaluated for antibacterial activity against a panel of 24 Gram positive (8) and Gram negative (16) bacteria. Based on minimum inhibitory concentration (MIC) scores, compounds 1 and 2 were shown to be specifically potent against Gram positive bacteria whereas compounds 3 and, to a lesser extent, 4 exhibited broad range activity. All four compounds were active against methicillin resistant Staphylococcus aureus (MRSA). Time kill assays revealed the compounds to exhibit both time- and concentration-dependent pharmacokinetics against susceptible bacteria. Each compound was bactericidal against one or more bacteria with 3 being especially potent after 8h exposure; compounds 1 and 3 were bactericidal against MRSA. Compound 3 was the most effective bactericide across the series especially toward B. subtilis, S. saprophyticus, A. hydrophila, P. vulgaris, and V. parahaemolyticus. This study demonstrates the potential of this class of compounds as antibacterial agents, either broad range or against specific bacteria.
Asunto(s)
Antibacterianos , Bacterias Grampositivas/crecimiento & desarrollo , Compuestos Orgánicos de Oro , Tiocarbamatos , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Compuestos Orgánicos de Oro/síntesis química , Compuestos Orgánicos de Oro/química , Compuestos Orgánicos de Oro/farmacología , Tiocarbamatos/síntesis química , Tiocarbamatos/química , Tiocarbamatos/farmacologíaRESUMEN
Like chiral organic drugs, the chemical and biological properties of metal complexes can be dependent on chirality. Two pairs of [Cu(phen)(ala)(H2O)]X·xH2O (phen=1.10-phenanthroline: X=NO3(-); ala: l-alanine (l-ala), 1 and d-alanine (d-ala) 2; and (X=Cl(-); ala: l-ala, 3 and d-ala, 4) complex salts (x=number of lattice water molecules) have been synthesized and characterized. The crystal structure of 3 has been determined. The same pair of enantiomeric species, viz. [Cu(phen)(l-ala)(H2O)](+) and [Cu(phen)(d-ala)(H2O)](+), have been identified to be present in the aqueous solutions of both 1 and 3, and in those of both 2 and 4 respectively. Both 3 and 4 bind more strongly to ds(AT)6 than ds(CG)6. There is no or insignificant effect of the chirality of 3 and 4 on the production of hydroxyl radicals, binding to deoxyribonucleic acid from calf thymus (CT-DNA), ds(CG)6, G-quadruplex and 17-base pair duplex, and inhibition of both topoisomerase I and proteasome. Among the three proteasome proteolytic sites, the trypsin-like site is inhibited most strongly by these complexes. However, the chirality of 3 and 4 does affect the number of restriction enzymes inhibited, and their binding constants towards ds(AT)6 and serum albumin.
Asunto(s)
Alanina/química , Complejos de Coordinación/química , Cobre/química , ADN/química , Complejo de la Endopetidasa Proteasomal/química , Piridinas/química , Animales , Cationes Bivalentes , Bovinos , Complejos de Coordinación/síntesis química , ADN-Topoisomerasas de Tipo I/química , Humanos , Radical Hidroxilo/química , Fenantrolinas/química , Proteolisis , Albúmina Sérica/química , Estereoisomerismo , Inhibidores de Topoisomerasa I/químicaRESUMEN
In the solid state each of three binuclear zinc dithiocarbamates bearing hydroxyethyl groups, {Zn[S2CN(R)CH2CH2OH]2}2 for R = iPr (1), CH2CH2OH (2), and Me (3), and an all alkyl species, [Zn(S2CNEt2)2]2 (4), features a centrosymmetric {ZnSCS}2 core with a step topology; both 1 and 3 were isolated as monohydrates. All compounds were broadly cytotoxic, specifically against human cancer cell lines compared with normal cells, with greater potency than cisplatin. Notably, some selectivity were indicated with 2 being the most potent against human ovarian carcinoma cells (cisA2780), and 4 being more cytotoxic toward multidrug resistant human breast carcinoma cells (MCF-7R), human colon adenocarcinoma cells (HT-29), and human lung adenocarcinoma epithelial cells (A549). Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis in HT-29 cells is demonstrated via both extrinsic and intrinsic pathways. Compounds 2-4 activate the p53 gene while 1 activates both p53 and p73. Cell cycle arrest at the S and G2/M phases correlates with inhibition of HT-29 cell growth. Cell invasion is also inhibited by 1-4 which is correlated with down-regulation of NF-κB.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Tiocarbamatos/farmacología , Inhibidores de Topoisomerasa I/farmacología , Zinc/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/toxicidad , Genes p53 , Humanos , FN-kappa B/genética , Invasividad Neoplásica , ARN Mensajero/genética , Ratas , Tiocarbamatos/síntesis química , Tiocarbamatos/química , Tiocarbamatos/toxicidad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/toxicidadRESUMEN
The phosphanegold(I) carbonimidothioates, Ph3PAu{SC(OR)=NC6H4Me-4} for R = Me (1), Et (2) and iPr (3), feature linear P-Au-S coordination geometries and exhibit potent in vitro cytotoxicity against HT-29 colon cancer cells in both monolayer and multi-cellular spheroid models (e.g., IC50 = 11.9 ± 0.4 and 20.3 ± 0.3 µM for 2, respectively). Both intrinsic and extrinsic pathways of apoptosis are demonstrated by human apoptosis PCR array analysis, caspase activities, DNA fragmentation and cell apoptotic assays. Compounds 1-3 induce an extrinsic pathway that leads to down-regulation of NFκB. Compound 2 also exhibits an extrinsic apoptotic pathway involving the activation of both p53 and p73, whereas 3 activates p53 only. Lys48- and Lys63-linked polyubiquitination are also promoted by 1-3. Each of cytotoxic Ph3PAu{SC(OR)=NC6H4Me-4}, for R = Me (1), Et (2) and iPr (3), induce an intrinsic apoptotic pathway as well as an extrinsic pathway leading to down-regulation of NFκB. Lys48- and Lys63-linked polyubiquitination are promoted by 1-3 and these are able to inhibit cell invasion and to suppress the activity of TrxR.
Asunto(s)
Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , FN-kappa B/metabolismo , Compuestos Orgánicos de Oro/farmacología , Fosfinas/farmacología , Compuestos de Sulfhidrilo/farmacología , Ubiquitinación/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Células HT29 , Humanos , Estructura Molecular , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & control , Compuestos Orgánicos de Oro/síntesis química , Compuestos Orgánicos de Oro/química , Fosfinas/química , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/químicaRESUMEN
The compound with R=CH2CH3 in Bi(S2CNR2)3 (1) is highly cytotoxic against a range of human carcinoma, whereas that with R=CH2CH2OH (2) is considerably less so. Both 1 and 2 induce apoptosis in HepG2 cells with some evidence for necrosis induced by 2. Based on DNA fragmentation, caspase activities and human apoptosis PCR-array analysis, both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. While both compounds activate mitochondrial and FAS apoptotic pathways, compound 1 was also found to induce another death receptor-dependent pathway by induction of CD40, CD40L and TNF-R1 (p55). Further, 1 highly expressed DAPK1, a tumour suppressor, with concomitant down-regulation of XIAP and NF-κB. Cell cycle arrest at the S and G2/M phases correlates with the inhibition of the growth of HepG2 cells. The cell invasion rate of 2 is 10-fold higher than that of 1, a finding correlated with the down-regulation of survivin and XIAP expression by 1. Compounds 1 and 2 interact with DNA through different binding motifs with 1 interacting with AT- or TA-specific sites followed by inhibition of restriction enzyme digestion; 2 did not interfere with any of the studied restriction enzymes.
Asunto(s)
Antineoplásicos/farmacología , Bismuto/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , FN-kappa B/metabolismo , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Apoptosis/genética , Permeabilidad de la Membrana Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proteínas Quinasas Asociadas a Muerte Celular/genética , Ensayos de Selección de Medicamentos Antitumorales/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2/efectos de los fármacos , Humanos , Transducción de Señal/efectos de los fármacos , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
The synthesis and characterisation of R3PAu[S2CN((i)Pr)CH2CH2OH], for R = Ph (1), Cy (2) and Et (3)4, is reported. Compounds 1-3 are cytotoxic against the doxorubicin-resistant breast cancer cell line, MCF-7R, with 1 exhibiting greater potency and cytotoxicity than either of doxorubicin and cisplatin. Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis by 1, and necrosis by 2 and 3, are demonstrated, by both extrinsic and intrinsic pathways. Compound 1 activates the p53 gene, 2 activates only the p73 gene, whereas 3 activates both the p53 and p73 genes. Compounds 1 and 3 activate NF-κB, and each inhibits topoisomerase I.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Orgánicos de Oro/farmacología , Fosfinas/química , Tiocarbamatos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Compuestos Orgánicos de Oro/síntesis química , Compuestos Orgánicos de Oro/química , Relación Estructura-ActividadRESUMEN
The Ph3PAu[SC(OR)=NPh], R=Me (1), Et (2) and iPr (3), compounds are significantly cytotoxic to the HT-29 cancer cell line with 1 being the most active. Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis is demonstrated and both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. Compound 1 activates the p73 gene, whereas each of 2 and 3 activates the p53 gene. An additional apoptotic mechanism is exhibited by 2, that is, via the JNK/MAP pathway.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Compuestos Orgánicos de Oro/química , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células HT29 , Humanos , Modelos Moleculares , Compuestos Orgánicos de Oro/farmacología , Estándares de ReferenciaRESUMEN
The binding site specificity of the ternary complexes, [M(II)(phen)(edda)] (M(II) = Pt(2+) and Zn(2+); phen = 1,10-phenanthroline; edda = N,N'-ethylenediaminediacetic acid), for the self-complementary oligonucleotides (ODNs), ds(C(1)G(2)C(3)G(4)A(5)A(6)T(7)T(8)C(9)G(10)C(11)G(12))(2) (ODN1) and ds(C(1)G(2)C(3)G(4)T(5)A(6)T(7)A(8)C(9)G(10)C(11)G(12))(2) (ODN2), was studied by NMR measurements. The results indicated that [Pt(ii)(phen)(edda)] was partially intercalated between C(3)/G(10) and G(4)/C(9) base pairs of ODN1 and ODN2 in the major grooves, whereas [Zn(II)(phen)(edda)] was bound specifically to the TATA region of ODN2 in the minor groove and to the terminal G(2)/C(11) base pair of ODN1 in the major groove. The preference for the TATA sequence over the AATT sequence in the binding of [Zn(phen)(edda)] was attributed to the wider minor groove width of the TATA sequence. The bindings of the complexes to ct-DNA were also studied by UV, CD, and fluorescence spectroscopy. Additionally, the antiproliferative property of [Pt(II)(phen)(edda)] towards MCF7 breast cancer cells and normal MCF10-A cells was compared with that of [Zn(II)(phen)(edda)].
Asunto(s)
Complejos de Coordinación/química , ADN/química , Ácido Edético/análogos & derivados , Fenantrolinas/química , Platino (Metal)/química , Zinc/química , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/toxicidad , ADN/metabolismo , Ácido Edético/química , Humanos , Células MCF-7RESUMEN
Two ternary Zn(II) complexes, with 1,10-phenanthroline (phen) as the main ligand and a carboxylate-containing ligand [dipicolinate (dipico) or L-threoninate (L-Thr)] as the subsidiary ligand, were prepared and characterized by elemental analysis, Fourier transform IR, UV, and fluorescence spectroscopy, X-ray diffraction, molar conductivity, and electrospray ionization mass spectrometry. X-ray structure analysis shows that both [Zn(phen)(dipico)(H(2)O)]·H(2)O (1) and [Zn(phen)(L-Thr)(H(2)O)Cl]·2H(2)O (2) have octahedral geometry about the Zn(II) atom. Both complexes can inhibit topoisomerase I, and have better anticancer activity than cisplatin against nasopharyngeal cancer cell lines, HK1 and HONE-1, with concentrations causing 50 % inhibition of cell proliferation (IC(50)) in the low micromolar range. Complex 2 has the highest therapeutic index for HK1. Both Zn(II) complexes can induce cell death by apoptosis. Changing the subsidiary ligand in the Zn(II) complexes affects the UV-fluorescence spectral properties of the coordinated phen ligand, the binding affinity for some DNA sequences, nucleobase sequence-selective binding, the phase at which cell cycle progression was arrested for treated cancer cells, and their therapeutic index.
Asunto(s)
Antineoplásicos/síntesis química , Complejos de Coordinación/síntesis química , Fenantrolinas/química , Piridinas/química , Treonina/química , Zinc/química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/química , Cisplatino/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Fenantrolinas/farmacología , Espectroscopía Infrarroja por Transformada de Fourier , Inhibidores de Topoisomerasa/química , Inhibidores de Topoisomerasa/farmacologíaRESUMEN
A series of ternary copper(II)-1,10-phenanthroline complexes with glycine and methylated glycine derivatives, [Cu(phen)(aa)(H(2)O)]NO(3)·xH(2)O 1-4 (amino acid (aa): glycine (gly), 1; DL: -alanine (DL: -ala), 2; 2,2-dimethylglycine (C-dmg), 3; sarcosine (sar), 4), were synthesized and characterized by FTIR, elemental analysis, electrospray ionization-mass spectra (ESI-MS), UV-visible spectroscopy and molar conductivity measurement. The determined X-ray crystallographic structures of 2 and 3 show each to consist of distorted square pyramidal [Cu(phen)(aa)(H(2)O)](+) cation, a nitrate counter anion, and with or without lattice water, similar to previously reported structure of [Cu(phen)(gly)(H(2)O)]NO(3)·1½H(2)O. It is found that 1-4 exist as 1:1 electrolytes in aqueous solution, and the cationic copper(II) complexes are at least stable up to 24 h. Positive-ion ESI-MS spectra show existence of only undissociated [Cu(phen)(aa)](+) species. Electron paramagnetic resonance, gel electrophoresis, fluorescence quenching, and restriction enzyme inhibition assay were used to study the binding interaction, binding affinity and selectivity of these complexes for various types of B-form DNA duplexes and G-quadruplex. All complexes can bind selectively to DNA by intercalation and electrostatic forces, and inhibit topoisomerase I. The effect of the methyl substituents of the coordinated amino acid in the above complexes on these biological properties are presented and discussed. The IC(50) values (24 h) of 1-4 for nasopharyngeal cancer cell line HK1 are in the range 2.2-5.2 µM while the corresponding values for normal cell line NP69 are greater than 13.0 µM. All complexes, at 5 µM, induced 41-60 % apoptotic cell death in HK1 cells but no significant cell death in NP69 cells.
Asunto(s)
Antineoplásicos/farmacología , Cobre/farmacología , Compuestos Organometálicos/farmacología , Animales , Antineoplásicos/química , Línea Celular , Línea Celular Tumoral , Cobre/química , Cristalografía por Rayos X , ADN/química , ADN/efectos de los fármacos , Espectroscopía de Resonancia por Spin del Electrón , Glicina/análogos & derivados , Glicina/química , Glicina/farmacología , Humanos , Ligandos , Masculino , Compuestos Organometálicos/química , Espectrometría de Masa por Ionización de Electrospray , Espectroscopía Infrarroja por Transformada de Fourier , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/farmacologíaRESUMEN
By inhibiting only two or three of 12 restriction enzymes, the series of [M(phen)(edda)] complexes [M(II) is Cu, Co, Zn; phen is 1,10-phenanthroline; edda is N,N'-ethylenediaminediacetate] exhibit DNA binding specificity. The Cu(II) and Zn(II) complexes could differentiate the palindromic sequences 5'-CATATG-3' and 5'-GTATAC-3', whereas the Co(II) analogue could not. This and other differences in their biological properties may arise from distinct differences in their octahedral structures. The complexes could inhibit topoisomerase I, stabilize or destabilize G-quadruplex, and lower the mitochondrial membrane potential of MCF7 breast cells. The pronounced stabilization of G-quadruplex by the Zn(II) complex may account for the additional ability of only the Zn(II) complex to induce cell cycle arrest in S phase. On the basis of the known action of anticancer compounds against the above-mentioned individual targets, we suggest the mode of action of the present complexes could involve multiple targets. Cytotoxicity studies with MCF10A and cisplatin-resistant MCF7 suggest that these complexes exhibit selectivity towards breast cancer cells over normal ones.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , ADN de Neoplasias/química , Etilenodiaminas/química , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Fenantrolinas/química , Antineoplásicos/síntesis química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , ADN-Topoisomerasas de Tipo I/metabolismo , ADN de Neoplasias/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , G-Cuádruplex/efectos de los fármacos , Humanos , Modelos Moleculares , Compuestos Organometálicos/síntesis química , Relación Estructura-Actividad , Especificidad por Sustrato , Células Tumorales CultivadasRESUMEN
The synthesis and characterization of two cobalt(II) complexes, Co(phen)(ma)Cl 1 and Co(ma)(2)(phen) 2, (phen=1,10-phenanthroline, ma(-)=maltolate or 2-methyl-4-oxo-4H-pyran-3-olate) are reported herein. The complexes have been characterized by FTIR, CHN analysis, fluorescence spectroscopy, UV-visible spectroscopy, conductivity measurement and X-ray crystallography. The number of chelated maltolate ligands seems to influence their DNA recognition, topoisomerase I inhibition and antiproliferative properties.
Asunto(s)
Cobalto/química , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Fenantrolinas/química , Pironas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quelantes/síntesis química , Quelantes/química , Quelantes/farmacología , Cristalografía por Rayos X , ADN/química , ADN/metabolismo , ADN-Topoisomerasas de Tipo I/metabolismo , Femenino , Humanos , Concentración 50 Inhibidora , Ligandos , Compuestos Organometálicos/química , Análisis EspectralRESUMEN
Crystal structure analysis of the zinc complex establishes it as a distorted octahedral complex, bis(3-methylpicolinato-kappa(2) N,O)(2)(1,10-phenanthroline-kappa(2) N,N)-zinc(II) pentahydrate, [Zn(3-Me-pic)(2)(phen)]x5H(2)O. The trans-configuration of carbonyl oxygen atoms of the carboxylate moieties and orientation of the two planar picolinate ligands above and before the phen ligand plane seems to confer DNA sequence recognition to the complex. It cannot cleave DNA under hydrolytic condition but can slightly be activated by hydrogen peroxide or sodium ascorbate. Circular Dichroism and Fluorescence spectroscopic analysis of its interaction with various duplex polynucleotides reveals its binding mode as mainly intercalation. It shows distinct DNA sequence binding selectivity and the order of decreasing selectivity is ATAT > AATT > CGCG. Docking studies lead to the same conclusion on this sequence selectivity. It binds strongly with G-quadruplex with human tolemeric sequence 5'-AG(3)(T(2)AG(3))(3)-3', can inhibit topoisomerase I efficiently and is cytotoxic against MCF-7 cell line.
Asunto(s)
ADN Superhelicoidal/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Inhibidores de Topoisomerasa I , Antineoplásicos/química , Antineoplásicos/farmacología , Ácido Ascórbico/farmacología , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Cristalografía por Rayos X , División del ADN , ADN-Topoisomerasas de Tipo I/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Peróxido de Hidrógeno/farmacología , Modelos Químicos , Modelos Moleculares , Fenantrolinas/química , Ácidos Picolínicos/química , Plásmidos/química , Zinc/químicaRESUMEN
The binding selectivity of the M(phen)(edda) (M=Cu, Co, Ni, Zn; phen=1,10-phenanthroline, edda=ethylenediaminediacetic acid) complexes towards ds(CG)(6), ds(AT)(6) and ds(CGCGAATTCGCG) B-form oligonucleotide duplexes were studied by CD spectroscopy and molecular modeling. The binding mode is intercalation and there is selectivity towards AT-sequence and stacking preference for A/A parallel or diagonal adjacent base steps in their intercalation. The nucleolytic properties of these complexes were investigated and the factors affecting the extent of cleavage were determined to be: concentration of complex, the nature of metal(II) ion, type of buffer, pH of buffer, incubation time, incubation temperature, and the presence of hydrogen peroxide or ascorbic acid as exogenous reagents. The fluorescence property of these complexes and its origin were also investigated. The crystal structure of the Zn(phen)(edda) complex is reported in which the zinc atom displays a distorted trans-N(4)O(2) octahedral geometry; the crystal packing features double layers of complex molecules held together by extensive hydrogen bonding that inter-digitate with adjacent double layers via pi...pi interactions between 1,10-phenanthroline residues. The structure is compared with that of the recently described copper(II) analogue and, with the latter, included in molecular modeling.