RESUMEN
A ligand (HL) was synthesized from the pyridoxal hydrochloride (vitamin B6 form) and 1-(2-Aminoethyl)piperidine in one single step. The metal complexes [Zn(L)(Bpy)]NO3 (1), [Cu(L)(Bpy)]NO3 (2), and [Co(L)(Bpy)]NO3 (3) were prepared by tethering HL and 2,2'-bipyridine. The synthesized HL and metal complexes 1-3 were thoroughly characterized using spectroscopic techniques such as 1H NMR, 13C NMR, FTIR, EI-MS, molar conductance, and magnetic moment, in addition to CHN elemental analysis. The geometry of complexes was square pyramidal around the metal ions {Zn(II), Cu(II), and Co(II)}. The interaction of ligand and metal complexes with DNA and BSA macromolecules was accomplished by UV-Vis absorption and fluorescence spectroscopy in vitro. The hyperchromism in band at 303-325 with no shift supports the groove binding with some partial intercalation in grooves. Similarly, in BSA-binding studies, complex 2 shows greater binding potential in the hydrophobic core probably near the Trp-212 in the subdomain IIA. Furthermore, complex 2 shows excellent cytotoxicity on HepG2 cancer cells with IC50 = 25.0 ± 0.45 µM. The detailed analysis by cell-cycle studies shows cell arrest at the G2/M phase. The type of cell death was authenticated by an annexin V-FTIC dual staining experiment that reveals maximum death by apoptosis together with non-specific necrosis.
RESUMEN
A new ligand 1,2,4-triazino[5,6-b]indol-3-ylimino methyl naphthalene-2-ol (HL) was derived from 5H-[1,2,4]triazino[5,6-b]indol-3-amine and 2-hydroxy-1-naphthaldehyde. The metal complexes of the type [Ni(L)(Bipy)]1/2SO4 (1), [Cu(L)(Bipy)(H2O)2]1/2SO4 (2), [Ni(L)(Phen)]1/2SO4 (3) and [Cu(L)(Phen)(H2O)2]1/2SO4 (4) were synthesized. The ligand (HL) and complexes 1-4 were thoroughly characterized by elemental analysis and spectroscopic methods (FT-IR, ToF-MS, 1H NMR, 13C NMR), molar conductance and magnetic moment determination. The Ni(II) complexes 1 and 3 adopt the square planar geometry and Cu(II) complexes 2 and 4 acquire distorted octahedral arrangement. In vitro DNA binding behavior of ligand (HL) and metal complexes 1-4 was explored by fluorescence spectral and ethidium bromide studies. The outcomes reveal that the complexes interact with DNA via non-covalent groove binding and electrostatic interactions. The higher binding constant (K) values of 4.35 × 104 and 9.12 × 104 M-1 for complexes 2 and 4 indicate stronger binding ability with DNA. Moreover, in vitro human serum albumin (HSA) binding experiment with HL and complexes 1-4 reveals conformational modulations in the Trp-214 microenvironments in the subdomain IIA pocket.
Asunto(s)
Complejos de Coordinación , Albúmina Sérica Humana , Humanos , Ligandos , Complejos de Coordinación/farmacología , Espectroscopía Infrarroja por Transformada de Fourier , Naftalenos/farmacología , ADN , Bases de Schiff , CobreRESUMEN
The advent of the clinically approved drug cisplatin started a new era in the design of metallodrugs for cancer chemotherapy. However, to date, there has not been much success in this field due to the persistence of some side effects and multi-drug resistance of cancer cells. In recent years, there has been increasing interest in the design of metal chemotherapeutics using organometallic complexes due to their good stability and unique properties in comparison to normal coordination complexes. Their intermediate properties between that of traditional inorganic and organic materials provide researchers with a new platform for the development of more promising cancer therapeutics. Classical metal-based drugs exert their therapeutic potential by targeting only DNA, but in the case of organometallic complexes, their molecular target is quite distinct to avoid drug resistance by cancer cells. Some organometallic drugs act by targeting a protein or inhibition of enzymes such as thioredoxin reductase (TrRx), while some target mitochondria and endoplasmic reticulum. In this review, we mainly discuss organometallic complexes of Ru, Ti, Au, Fe and Os and their mechanisms of action and how new approaches improve their therapeutic potential towards various cancer phenotypes. Herein, we discuss the role of structure-reactivity relationships in enhancing the anticancer potential of drugs for the benefit of humans both in vitro and in vivo. Besides, we also include in vivo tumor models that mimic human physiology to accelerate the development of more efficient clinical organometallic chemotherapeutics.
RESUMEN
New copper(II)-based complex (1) was synthesized and characterized by analytical, spectroscopic and single crystal X-ray diffraction. The in vitro binding studies of complex 1 with CT DNA and HSA have been investigated by employing biophysical techniques to examine the binding propensity of 1 towards DNA and HSA. The results showed that 1 avidly binds to CT DNA via electrostatic mode along with the hydrogen bonding interaction of NH2 and CN groups of Schiff base ligand with the base pairs of DNA helix, leads to partial unwinding and destabilization of the DNA double helix. Moreover, the CD spectral studies revealed that complex 1 binds through groove binding interaction that stabilizes the right-handed B-form of DNA. Complex 1 showed an impressive photoinduced nuclease activity generating single-strand breaks in comparison with the DNA cleavage activity in presence of visible light. The mechanistic investigation revealed the efficiency of 1 to cleave DNA strands by involving the generation of reactive oxygen species. Furthermore, the time dependent DNA cleavage activity showed that there was gradual increase in the amount of NC DNA on increasing the photoexposure time. However, the interaction of 1 and HSA showed that the change of intrinsic fluorescence intensity of HSA was induced by the microenvironment of Trp residue.
Asunto(s)
Antineoplásicos/síntesis química , Complejos de Coordinación/síntesis química , Cobre/química , ADN/metabolismo , Plásmidos/metabolismo , Albúmina Sérica/metabolismo , Animales , Antineoplásicos/metabolismo , Benzaldehídos/química , Bovinos , Dicroismo Circular , Complejos de Coordinación/metabolismo , Cristalografía por Rayos X , Ciclohexilaminas/química , ADN/química , División del ADN/efectos de la radiación , Humanos , Ligandos , Luz , Conformación Molecular , Unión Proteica , Especies Reactivas de Oxígeno/metabolismo , Bases de Schiff/química , Albúmina Sérica/química , Espectrometría de Fluorescencia , Espectrofotometría Infrarroja , Rayos UltravioletaRESUMEN
New pharmacophore organoselenium compound (1) was designed, synthesized and characterized by various spectroscopic methods (IR, ESI-MS, (1)H, (13)C and (77)Se NMR) and further confirmed by X-ray crystallography. Compound 1 consists of two 3,5-bis(trifluoromethyl)phenyl units which are connected to the selenium atom via the organometallic C-Se bond. In vitro DNA binding studies of 1 was investigated by absorption and emission titration methods which revealed that 1 recognizes the minor groove of DNA in accordance with molecular docking studies with the DNA duplex. Gel electrophoretic assay demonstrates the ability of 1 to cleave pBR322 DNA through hydrolytic process which was further validated by T4 religation assay. To understand the drug-protein interaction of which ultimate molecular target was DNA, the affinity of 1 towards HSA was also investigated by the spectroscopic and molecular modeling techniques which showed hydrophobic interaction in the subdomain IIA of HSA. Furthermore, the intracellular localization of 1 was evidenced by cell imaging studies using HeLa cells.
Asunto(s)
ADN de Neoplasias/química , Compuestos de Organoselenio/farmacología , Albúmina Sérica/química , Neoplasias del Cuello Uterino/diagnóstico , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , División del ADN , ADN de Neoplasias/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Células HeLa , Humanos , Modelos Moleculares , Estructura Molecular , Compuestos de Organoselenio/química , Relación Estructura-ActividadRESUMEN
New copper(II) complex with Schiff base ligand 4-[(2-Hydroxy-3-methoxy-benzylidene)-amino]-benzoic acid (H2L) was synthesized and characterized by spectroscopic and analytical and single crystal X-ray diffraction studies which revealed that the complex 1 exist in a distorted octahedral environment. In vitro CT-DNA binding studies were performed by employing different biophysical technique which indicated that the 1 strongly binds to DNA in comparison to ligand via electrostatic binding mode. Complex 1 cleaves pBR322 DNA via hydrolytic pathway and recognizes minor groove of DNA double helix. The HSA binding results showed that ligand and complex 1 has ability to quench the fluorescence emission intensity of Trp 214 residue available in the subdomain IIA of HSA.
Asunto(s)
Cobre/química , División del ADN/efectos de los fármacos , ADN/metabolismo , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/metabolismo , Plásmidos/genética , Albúmina Sérica/metabolismo , Animales , Bovinos , Técnicas de Química Sintética , ADN/química , Humanos , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Conformación Proteica , Especies Reactivas de Oxígeno/farmacología , Bases de Schiff/química , Albúmina Sérica/química , Electricidad EstáticaRESUMEN
New Cu(II) complex 1 of indole-3-propionic acid and 1,10-phenanthroline was synthesized and characterized by analytical, spectroscopic and single crystal X-ray diffraction. In vitro DNA binding studies of 1 was performed by employing UV-vis and fluorescence spectroscopic techniques. The binding affinity towards human serum albumin (HSA) was also investigated to understand the carrier role in body system, as the time dependent HPLC experiment of 1 revealed that bonded drug with protein releases slowly in presence of DNA. Complex 1 exhibited good anti-tumor activity (GI50 values <10 µg/ml), and to elucidate the mechanism of tumor inhibition, topoisomerase I enzymatic activity was carried out and further validated by cell imaging studies which clearly showed its nuclear localization.
Asunto(s)
Cobre/química , División del ADN/efectos de los fármacos , ADN/metabolismo , Imagen Molecular , Compuestos Organometálicos/metabolismo , Compuestos Organometálicos/farmacología , Albúmina Sérica/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Técnicas de Química Sintética , Cristalografía por Rayos X , ADN/química , ADN-Topoisomerasas de Tipo I/metabolismo , Humanos , Indoles/química , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Fenantrolinas/química , Procesos Fotoquímicos , Plásmidos/genética , Conformación Proteica , Albúmina Sérica/químicaRESUMEN
New metal-based anticancer chemotherapeutic drug candidates [Cu(phen)L](NO3)2 (1) and [Zn(phen)L](NO3)2 (2) were synthesized from ligand L (derived from pharmacophore scaffold barbituric acid and pyrazole). In vitro DNA binding studies of the L, 1 and 2 were carried out by various biophysical techniques revealing electrostatic mode. Complex 1 cleaves pBR322 DNA via oxidative pathway and recognizes major groove of DNA double helix. The molecular docking study was carried out to ascertain the mode of action towards the molecular target DNA and enzymes. The complex 1 exhibited remarkably good anticancer activity on a panel of human cancer cell lines (GI50 values < 10 µg/ml), and to elucidate the mechanism of cancer inhibition, Topo-I enzymatic activity was carried out.
Asunto(s)
Antineoplásicos/farmacología , Cobre/química , ADN-Topoisomerasas de Tipo I/efectos adversos , Plásmidos , Inhibidores de Topoisomerasa I/farmacología , Antineoplásicos/química , Línea Celular Tumoral , ADN/efectos de los fármacos , Electroforesis en Gel de Agar , Humanos , Simulación del Acoplamiento Molecular , Especies Reactivas de Oxígeno/metabolismo , Análisis Espectral/métodos , Inhibidores de Topoisomerasa I/química , Difracción de Rayos XRESUMEN
New molecular topologies quercetin-Cu(II)-Sn2(IV) and Zn(II)-Sn2(IV)1 and 2 were designed and synthesized to act as potential cancer chemotherapeutic agents. Their interaction with CT DNA by UV-vis and fluorescence spectroscopy was evaluated revealing an electrostatic mode of binding. Quercetin complexes are capable of promoting DNA cleavage involving both single and double strand breaks. Complex 1 cleaved pBR322 DNA via an oxidative mechanism while 2 followed a hydrolytic pathway, accessible to the minor groove of the DNA double helix in accordance with molecular docking studies with the DNA duplex of sequence d(CGCGAATTCGCG)2 dodecamer demonstrating that the complex was stabilized by additional electrostatic and hydrogen bonding interactions with the DNA. ROS such as OHË, H2O2 and O2Ë(-) are the major metabolites responsible for chronic diseases such as cancer, respiratory disorders, HIV, and diabetes etc., therefore eliminating ROS by molecular scaffolds involving SOD enzymatic activity has emerged as a potential way to develop a novel class of drugs. Therefore, in vitro superoxide dismutase activity of redox active complex 1 was evaluated by using a xanthine/xanthine oxidase-NBT assay which showed an IC50 value of 2.26 µM. Moreover, the cytotoxicity of both the complexes were screened on a panel of human carcinoma cell lines (GI50 values <8.7 µM) which revealed that 1 has a better prospect of acting as a cancer chemotherapeutic agent, and to elucidate the mechanism of tumor inhibition, Topo-I enzymatic activity was carried out. Furthermore, molecular modeling studies were carried out to understand molecular features important for drug-enzyme interactions which offer new insights into the experimental model observations.
Asunto(s)
Antineoplásicos/farmacología , ADN-Topoisomerasas de Tipo I/metabolismo , ADN de Neoplasias/efectos de los fármacos , Compuestos Organometálicos/farmacología , Quercetina/química , Inhibidores de Topoisomerasa I/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cobre/química , División del ADN , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Células HeLa , Humanos , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Relación Estructura-Actividad , Superóxido Dismutasa/antagonistas & inhibidores , Superóxido Dismutasa/metabolismo , Estaño/química , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/química , Zinc/químicaRESUMEN
The monometallic (1-3) and heterobimetallic (4-6) complexes, containing 1,10-phenanthroline and indole-3-acetic acid were synthesized and characterized by spectroscopic (IR, UV-vis, NMR, ESI-MS) and analytical methods. The in vitro DNA binding studies of 5 and 6 with CT DNA were carried out by employing various biophysical methods which reveal strong electrostatic binding via phosphate backbone of DNA helix. The binding constant (K) value as determined from fluorescence experiments of complexes 5 and 6 were calculated to be 4.09×10(4) and 2.51×10(4) M(-1), respectively revealing that complex 5 has greater binding propensity for DNA. To gain further insight into the molecular recognition at the target site, interaction studies of 5 with 5'-GMP were carried out by employing (1)H and (31)P NMR spectroscopy. Complex 5 exhibited preferential selectively towards the minor groove of pBR322 DNA and efficient cleavage activity via hydrolytic pathway. Furthermore complexes 4-6 exhibited significant antimicrobial activity.