RESUMEN
Paclitaxel is a well-known cancer drug that functions as a mitotic inhibitor. This work focuses on a copper based crystal that encapsulates the pharmaceutical agent and serves as a drug delivery agent. A Copper10-Pacitaxil1 chloride (CU10PAC1) complex is synthesized and tested against the National Cancer Institute's sixty cell line panel. The 10:1 ratio results in a crystal that was examined by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spec (MALDI-TOF-MS), Scanning Electron Microscopy (SEM) and Proton (1H) and Carbon (13C) Nuclear Magnetic Resonance (NMR). The potential attributes of a copper based crystal as an in vivo drug carrier for Paclitaxel are discussed.
Asunto(s)
Cobre/química , Portadores de Fármacos/química , Paclitaxel/farmacología , Línea Celular Tumoral , Portadores de Fármacos/síntesis química , Liberación de Fármacos , Humanos , Oxidación-Reducción , Paclitaxel/químicaRESUMEN
The frontline tuberculosis (Tb) antibiotic isoniazid has been repurposed using a three component complex aimed at increasing the delivery efficiency and adding new avenues to its mechanism of action. This study focuses on pharmacokinetic studies of the isoniazid-sucrose-copper (II)-PEG-3350 complex. The assays include the Plasma Protein Binding Assay (85.8%), Caco-2 Permeability Assay (BâAPapp, 0.13 × 10-6 cm/s), Cytochrome P450 Inhibition Assay (i.e. CYP2B6, IC50 = 7.26 µM), In vitro microsomal Stability Assay (t1/2 NADPH-Dependent > 240 min), and HepG2 Cytotoxicity (no toxicity). The National Cancer Institute's 60 cell line panel is used to measure activity against cancer cells. The percent growth values averaged over all 60 cell lines indicates the complex has no anti-cancer activity, which also suggests a lack of general toxicity. It also provides data for the complexes specificity against Mycobacterium tuberculosis.
Asunto(s)
Antituberculosos/farmacocinética , Complejos de Coordinación/farmacocinética , Cobre/química , Inhibidores del Citocromo P-450 CYP2B6/farmacocinética , Mucosa Intestinal/metabolismo , Isoniazida/farmacocinética , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/química , Antituberculosos/toxicidad , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/toxicidad , Inhibidores del Citocromo P-450 CYP2B6/química , Inhibidores del Citocromo P-450 CYP2B6/toxicidad , Composición de Medicamentos , Semivida , Células Hep G2 , Humanos , Absorción Intestinal , Isoniazida/análogos & derivados , Isoniazida/química , Isoniazida/toxicidad , PermeabilidadRESUMEN
The copper(II) cation, sucrose, and hydroxychloroquine were complexed with the chemotherapy agent paclitaxel and studied for medicinal activity. Data (GI50, LD50) from single dose and five dose National Cancer Institute sixty cell line panels are presented. Analytical measurements of different complexes were made using Nuclear Magnetic Resonance (1H NMR), Matrix Assisted Laser Desorption Ionization-Time of Flight-Mass Spectrometry (MALDI-TOF-MS) and Fourier Transform-Ion Cyclotron Resonance (FT-ICR). Molecular modeling is utilized to better understand the impact that species could have on physical parameters associated with Lipinski's Rule of Five, such as logP and TPSA. On average, Cu(II) and hydroxychloroquine decreased GI50 values, while sucrose increased GI50 values of paclitaxel.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Compuestos Organometálicos/farmacología , Paclitaxel/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cobre/química , Cobre/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidroxicloroquina/química , Hidroxicloroquina/farmacología , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Paclitaxel/síntesis química , Paclitaxel/química , Relación Estructura-Actividad , Sacarosa/química , Sacarosa/farmacologíaRESUMEN
Bryostatin-1 is a marine natural product that has demonstrated medicinal activity in pre-clinical and clinical trials for the treatment of cancer, Alzheimer's disease, effects of stroke, and HIV. In this study, iron-bryostatin-1 was obtained using a pharmaceutical aquaculture technique developed by our lab that cultivates marine bacteria for marine natural product extraction. Analytical measurements (1)H and (13)C NMR, mass spectrometry, and flame atomic absorption were utilized to confirm the presence of an iron-bryostatin-1 complex. The iron-bryostatin-1 complex produced was then tested against the National Cancer Institute's 60 cell line panel. Adding iron to bryostatin-1 lowered the anti-cancer efficacy of the compound.
Asunto(s)
Antineoplásicos/farmacología , Brioestatinas/química , Brioestatinas/farmacología , Hierro/química , Antineoplásicos/química , Brioestatinas/aislamiento & purificación , Brioestatinas/metabolismo , Línea Celular Tumoral , Humanos , Espectroscopía de Resonancia Magnética , Técnicas MicrobiológicasRESUMEN
The bacterium responsible for causing tuberculosis is increasing its resistance to antibiotics resulting in new multidrug-resistant Mycobacterium tuberculosis (MDR-TB) and extensively drug-resistant M. tuberculosis (XDR-TB) strains. In this study, several analytical techniques including NMR, FT-ICR, MALDI-MS, and LCMS are used to study different aspects of the Copperpolyethylene glycol (PEG)Amikacin complex. The Cu(II) cation and the aggregate formed by PEG serve as a carrier for the antibiotic. Several CuPEGAmikacin complex variations were tested against NIH-NIAID cell lines containing both resistant and nonresistant strains of M. tuberculosis.
Asunto(s)
Amicacina/química , Complejos de Coordinación/química , Cobre/química , Polietilenglicoles/química , Complejos de Coordinación/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Mycobacterium tuberculosis/efectos de los fármacosRESUMEN
The bacterium responsible for causing tuberculosis has evolved resistance to antibiotics used to treat the disease, resulting in new multidrug resistant Mycobacterium tuberculosis (MDR-TB) and extensively drug resistant M. tuberculosis (XDR-TB) strains. Analytical techniques (1)H and (13)C Nuclear Magnetic Resonance (NMR), Fourier Transform-Ion Cyclotron Resonance with Electrospray Ionization (FT-ICR/ESI), and Matrix Assisted Laser Desorption Ionization-Mass Spectrometry (MALDI-TOF-MS) were used to study different aspects of the Cu(II)-polyethylene glycol (PEG-3350)-sucrose-isoniazid and Cu(II)-polyethylene glycol (PEG3350)-glucose-isoniazid complexes. The Cu(II) cation, sucrose or glucose, and the aggregate formed by PEG primarily serve as a composite drug delivery agent for the frontline antibiotic, however the improvement in MIC values produced with the CU-PEG-SUC-INH complex suggest an additional effect. Several Cu-PEG-SUC-INH complex variations were tested against INH resistant and nonresistant strains of M. tuberculosis.
Asunto(s)
Antituberculosos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Isoniazida/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/síntesis química , Antituberculosos/química , Relación Dosis-Respuesta a Droga , Isoniazida/síntesis química , Isoniazida/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The bacterium responsible for tuberculosis is increasing its resistance to antibiotics resulting in new multidrug-resistant Mycobacterium tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). In this study, several analytical techniques including NMR, FT-ICR, MALDI-MS, LC-MS and UV/Vis are used to study the copper-Rifampicin-Polyethylene glycol (PEG-3350) complex. The copper (II) cation is a carrier for the antibiotic Rifampicin as well as nutrients for the bacterium. The NIH-NIAID cell line containing several Tb strains (including antibiotic resistant strains) is tested against seven copper-PEG-RIF complex variations.
Asunto(s)
Antituberculosos/química , Cobre/química , Polietilenglicoles/química , Rifampin/química , Antituberculosos/análisis , Antituberculosos/farmacología , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
In recent years, the bacterium responsible for tuberculosis has been increasing its resistance to antibiotics resulting in new multidrug resistant Mycobacterium tuberculosis (MR-TB) and extensively drug-resistant tuberculosis (XDR-TB). In this study we use several analytical techniques including NMR, FT-ICR, TOF-MS, LC-MS and UV/Vis to study the copper-capreomycin complex. The copper (II) cation is used as a carrier for the antibiotic capreomycin. Once this structure was studied using NMR, FT-ICR, and MALDI-TOF-MS, the NIH-NIAID tuberculosis cell line for several Tb strains (including antibiotic resistant strains) were tested against up to seven variations of the copper-capreomycin complex. Different variations of copper improved the efficacy of capreomycin against Tb up to 250 fold against drug resistant strains of Tb.
Asunto(s)
Capreomicina/química , Capreomicina/farmacología , Cobre , Farmacorresistencia Bacteriana/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Antibióticos Antituberculosos/química , Antibióticos Antituberculosos/farmacología , Cobre/química , Iones , Estructura Molecular , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
A number of delivery agents, such as proteins, liposomes, micelles, and nanoparticles, are utilized for transporting pharmaceutical agents in a physiological environment. This Letter focuses on the use of the copper(II) ion and its potential role as a delivery agent for the taxanes and taxol couple to a malaria drug. Nuclear magnetic resonance (NMR, (1)H, (13)C, (15)N), Mass Spectrometry (LC-MS, MALDI-TOF, FT-ICR) and computational methods are used to examine the structure of the complex. The National Cancer Institute's benchmark 60 cell line panel is used to compare the efficacy of the copper-taxol and copper-taxol-hydroxychloroquin complexes to that of iron-taxol and pure taxol.
Asunto(s)
Antimaláricos/química , Antineoplásicos/química , Cobre/química , Portadores de Fármacos/química , Compuestos Organometálicos/química , Taxoides/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidroxicloroquina/química , Iones/química , Estructura Molecular , Compuestos Organometálicos/síntesis química , Paclitaxel/química , Relación Estructura-ActividadRESUMEN
In the first phase of this study, the binding of hydroxychloroquine to the copper(II) cation is examined using liquid chromatography-mass spectrometry (LC-MS), matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS), Fourier transform-ion cyclotron resonance spectrometry (FT-ICR) and nuclear magnetic resonance ((1)H and (13)C NMR) in one and two dimensions. The data suggest the metal-ligand complex is a polarity adaptive molecule. In the second phase of the study, the complexes activity is tested against the National Cancer Institute's 60 cell line panel. Its anti-cancer activity is compared to quinine, Cu(II)-quinine and hydroxychloroquine. It serves as a base line for future anti-cancer complexes in which hydroxychloroquine is utilized for its ability to impact cell autophagy.
Asunto(s)
Cobre/química , Hidroxicloroquina/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
The traditional NMR-based method for determining oligomeric protein structure usually involves distinguishing and assigning intra- and intersubunit NOEs. This task becomes challenging when determining symmetric homo-dimer structures because NOE cross-peaks from a given pair of protons occur at the same position whether intra- or intersubunit in origin. While there are isotope-filtering strategies for distinguishing intra from intermolecular NOE interactions in these cases, they are laborious and often prove ineffectual in cases of weak dimers, where observation of intermolecular NOEs is rare. Here, we present an efficient procedure for weak dimer structure determination based on residual dipolar couplings (RDCs), chemical shift changes upon dilution, and paramagnetic surface perturbations. This procedure is applied to the Northeast Structural Genomics Consortium protein target, SeR13, a negatively charged Staphylococcus epidermidis dimeric protein (K(d) 3.4 ± 1.4 mM) composed of 86 amino acids. A structure determination for the monomeric form using traditional NMR methods is presented, followed by a dimer structure determination using docking under orientation constraints from RDCs data, and scoring under residue pair potentials and shape-based predictions of RDCs. Validation using paramagnetic surface perturbation and chemical shift perturbation data acquired on sample dilution is also presented. The general utility of the dimer structure determination procedure and the possible relevance of SeR13 dimer formation are discussed.