RESUMEN
Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in ß-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.
Asunto(s)
Anemia de Células Falciformes , Antidrepanocíticos , Hemoglobina Fetal , Factores de Transcripción de Tipo Kruppel , Proteínas del Tejido Nervioso , Animales , Humanos , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/metabolismo , Antidrepanocíticos/química , Antidrepanocíticos/farmacología , Antidrepanocíticos/uso terapéutico , Cristalografía por Rayos X , Descubrimiento de Drogas , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Macaca fascicularis , Proteínas del Tejido Nervioso/metabolismo , Proteolisis/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
A newly identified epigenetic modifier increases fetal hemoglobin in preclinical studies.
Asunto(s)
Anemia de Células Falciformes , Antidrepanocíticos , Epigénesis Genética , Hemoglobina Fetal , Animales , Humanos , Ratones , Anemia de Células Falciformes/tratamiento farmacológico , Epigénesis Genética/efectos de los fármacos , Hemoglobina Fetal/genética , Antidrepanocíticos/química , Antidrepanocíticos/farmacología , Antidrepanocíticos/uso terapéutico , Descubrimiento de DrogasRESUMEN
The Kca3.1 channels, previously designated as IK1 or SK4 channels and encoded by the KCNN4 gene, are activated by a rise of the intracellular Ca2+ concentration. These K+ channels are widely expressed in many organs and involved in many pathologies. In particular, Kca3.1 channels have been studied intensively in the context of cancer. They are not only a marker and a valid prognostic tool for cancer patients, but have an important share in driving cancer progression. Their function is required for many characteristic features of the aggressive cancer cell behavior such as migration, invasion and metastasis as well as proliferation and therapy resistance. In the context of cancer, another property of Kca3.1 is now emerging. These channels can be a target for novel small molecule-based imaging probes, as it has been validated in case of fluorescently labeled senicapoc-derivatives. The aim of this review is (i) to give an overview on the role of Kca3.1 channels in cancer progression and in shaping the cancer microenvironment, (ii) discuss the potential of using Kca3.1 targeting drugs for cancer imaging, (iii) and highlight the possibility of combining molecular dynamics simulations to image inhibitor binding to Kca3.1 channels in order to provide a deeper understanding of Kca3.1 channel pharmacology. Alltogether, Kca3.1 is an attractive therapeutic target so that senicapoc, originally developed for the treatment of sickle cell anemia, should be repurposed for the treatment of cancer patients.
Asunto(s)
Acetamidas/uso terapéutico , Antineoplásicos/uso terapéutico , Calcio/metabolismo , Neoplasias/tratamiento farmacológico , Bloqueadores de los Canales de Potasio/uso terapéutico , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/antagonistas & inhibidores , Compuestos de Tritilo/uso terapéutico , Antineoplásicos/química , Antidrepanocíticos/química , Antidrepanocíticos/uso terapéutico , Sitios de Unión , Señalización del Calcio , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Simulación de Dinámica Molecular , Terapia Molecular Dirigida/métodos , Metástasis de la Neoplasia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Bloqueadores de los Canales de Potasio/química , Estructura Secundaria de Proteína , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/química , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genética , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genéticaRESUMEN
Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the ß-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30-40 years ago up to more promising 12- and 15-mers under consideration in recent years.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos , Diseño de Fármacos , Péptidos , Anemia de Células Falciformes/metabolismo , Anemia de Células Falciformes/patología , Antidrepanocíticos/química , Antidrepanocíticos/uso terapéutico , Hemoglobina Falciforme/metabolismo , Humanos , Péptidos/química , Péptidos/uso terapéuticoAsunto(s)
Anemia de Células Falciformes/prevención & control , Antidrepanocíticos/química , Benzaldehídos/química , Eritrocitos/química , Hemoglobina Falciforme/química , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Antidrepanocíticos/metabolismo , Benzaldehídos/farmacología , Cristalografía por Rayos X , Eritrocitos/metabolismo , Hemoglobina Falciforme/metabolismo , Humanos , Conformación ProteicaRESUMEN
Increasing the affinity of hemoglobin for oxygen represents a feasible and promising therapeutic approach for sickle cell disease by mitigating the primary pathophysiological event, i.e. the hypoxia-induced polymerization of sickle hemoglobin (Hb S) and the concomitant erythrocyte sickling. Investigations on a novel synthetic antisickling agent, SAJ-310, with improved and sustained antisickling activity have previously been reported. To further enhance the biological effects of SAJ-310, a structure-based approach was employed to modify this compound to specifically inhibit Hb S polymer formation through interactions which perturb the Hb S polymer-stabilizing αF-helix, in addition to primarily increasing the oxygen affinity of hemoglobin. Three compounds, TD-7, TD-8 and TD-9, were synthesized and studied for their interactions with hemoglobin at the atomic level, as well as their functional and antisickling activities in vitro. X-ray crystallographic studies with liganded hemoglobin in complex with TD-7 showed the predicted mode of binding, although the interaction with the αF-helix was not as strong as expected. These findings provide important insights and guidance towards the development of molecules that would be expected to bind and make stronger interactions with the αF-helix, resulting in more efficacious novel therapeutics for sickle cell disease.
Asunto(s)
Benzaldehídos/química , Hemoglobina Falciforme/efectos de los fármacos , Estabilidad Proteica/efectos de los fármacos , Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/síntesis química , Antidrepanocíticos/química , Antidrepanocíticos/farmacología , Benzaldehídos/farmacología , Benzaldehídos/uso terapéutico , Cristalografía por Rayos X , Hemoglobina Falciforme/química , Humanos , Ligandos , Polimerizacion/efectos de los fármacos , Unión ProteicaRESUMEN
Hypoxia-induced polymerization of sickle hemoglobin (Hb S) is the principal phenomenon that underlays the pathophysiology and morbidity associated with sickle cell disease (SCD). Opportunely, as an allosteric protein, hemoglobin (Hb) serves as a convenient and potentially critical druggable target. Consequently, molecules that prevent Hb S polymerization (Hb modifiers), and the associated erythrocyte sickling have been investigated-and retain significant interest-as a viable therapeutic strategy for SCD. This group of molecules, including aromatic aldehydes, form high oxygen affinity Schiff-base adducts with Hb S, which are resistant to polymerization. Here, we report the design and synthesis of novel potent antisickling agents (SAJ-009, SAJ-310 and SAJ-270) based on the pharmacophore of vanillin and INN-312, a previously reported pyridyl derivative of vanillin. These novel derivatives exhibited superior in vitro binding and pharmacokinetic properties compared to vanillin, which translated into significantly enhanced allosteric and antisickling properties. Crystal structure studies of liganded Hb in the R2 quaternary state in complex with SAJ-310 provided important insights into the allosteric and antisickling properties of this group of compounds. While these derivatives generally show similar in vitro biological potency, significant structure-dependent differences in their biochemical profiles would help predict the most promising candidates for successful in vivo pre-clinical translational studies and inform further structural modifications to improve on their pharmacologic properties.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/farmacología , Benzaldehídos/farmacología , Hemoglobina Falciforme/metabolismo , Piridinas/farmacología , Antidrepanocíticos/síntesis química , Antidrepanocíticos/química , Antidrepanocíticos/metabolismo , Benzaldehídos/síntesis química , Benzaldehídos/química , Benzaldehídos/metabolismo , Sangre/metabolismo , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Unión Proteica , Conformación Proteica , Subunidades de Proteína , Piridinas/síntesis química , Piridinas/química , Piridinas/metabolismo , Relación Estructura-ActividadAsunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Benzaldehídos/uso terapéutico , Hemoglobina Falciforme/análisis , Pirazinas/uso terapéutico , Pirazoles/uso terapéutico , Administración Oral , Adulto , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/sangre , Antidrepanocíticos/química , Benzaldehídos/administración & dosificación , Benzaldehídos/química , Cromatografía Líquida de Alta Presión , Humanos , Masculino , Pirazinas/administración & dosificación , Pirazinas/química , Pirazoles/administración & dosificación , Pirazoles/químicaRESUMEN
INTRODUCTION: Sickle cell disease is characterized by a point mutation involving substitution of glutamic acid at position 6 to valine. Encoded in this hydrophobic mutation is both an intrinsic capacity for the beta globin molecules to assemble into thermodynamically favoured polymeric states as well as a rational way of interrupting the aggregation. METHODS: In this work, starting with a theoretical model that employs occlusive binding onto the beta globin aggregation surface and using a range of computational methods and an effective energy for screening, a number of FDA approved drugs with computed aggregation inhibitory activities were identified. RESULTS AND CONCLUSION: The validity of the model was confirmed using sickling tests, after which pharmacophore models as well the structural basis for the observed antisickling effects were identified.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/química , Antidrepanocíticos/farmacología , Reposicionamiento de Medicamentos , Agregado de Proteínas/efectos de los fármacos , Globinas beta/metabolismo , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/metabolismo , Aprobación de Drogas , Reposicionamiento de Medicamentos/métodos , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Mutación Puntual , Estados Unidos , United States Food and Drug Administration , Globinas beta/genéticaRESUMEN
The pathophysiology of sickle cell disease (SCD) is dependent on the polymerization of deoxygenated sickle hemoglobin (HbS), leading to erythrocyte deformation (sickling) and vaso-occlusion within the microvasculature. Following deoxygenation, there is a delay time before polymerization is initiated, during which nucleation of HbS monomers occurs. An agent with the ability to extend this delay time or slow polymerization would therefore hold a therapeutic, possibly curative, potential. We used the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) method to screen for HbS-binding RNA aptamers modified with nuclease-resistant 2'-fluoropyrimidines. Polymerization assays were employed to identify aptamers with polymerization-inhibitory properties. Two noncompeting aptamers, DE3A and OX3B, were found to bind hemoglobin, significantly increase the delay time, and reduce the rate of polymerization of HbS. These modifiable, nuclease-resistant aptamers are potential new therapeutic agents for SCD.
Asunto(s)
Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/química , Aptámeros de Nucleótidos/química , Hemoglobina Falciforme/química , Polimerizacion/efectos de los fármacos , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/metabolismo , Antidrepanocíticos/síntesis química , Aptámeros de Nucleótidos/administración & dosificación , Aptámeros de Nucleótidos/síntesis química , Sistema Libre de Células , ADN Complementario , Nucleótidos de Desoxicitosina/química , Nucleótidos de Desoxiuracil/química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas/métodos , Humanos , Pirimidinas/química , Técnica SELEX de Producción de Aptámeros/métodosRESUMEN
Sickle cell disease (SCD) is a genetic blood disorder that affects the shape and transportation of red blood cells (RBCs) in blood vessels, leading to various clinical complications. Many drugs that are available for treating the disease are insufficiently effective, toxic, or too expensive. Therefore, there is a pressing need for safe, effective, and inexpensive therapeutic agents from indigenous plants used in ethnomedicines. The potential of aqueous extracts of Cajanus cajan leaf and seed, Zanthoxylum zanthoxyloides leaf, and Carica papaya leaf in sickle cell disease management was investigated in vitro using freshly prepared 2% sodium metabisulfite for sickling induction. The results indicated that the percentage of sickled cells, which was initially 91.6% in the control, was reduced to 29.3%, 41.7%, 32.8%, 38.2%, 47.6%, in the presence of hydroxyurea, C. cajan seed, C. cajan leaf, Z. zanthoxyloides leaf, and C. papaya leaf extracts, respectively, where the rate of polymerization inhibition was 6.5, 5.9, 8.0, 6.6, and 6.0 (×10-2) accordingly. It was also found that the RBC resistance to hemolysis was increased in the presence of the tested agents as indicated by the reduction of the percentage of hemolyzed cells from 100% to 0%. The phytochemical screening results indicated the presence of important phytochemicals including tannins, saponins, alkaloids, flavonoids, and glycosides in all the plant extracts. Finally, gas chromatography-mass spectrometry analysis showed the presence of important secondary metabolites in the plants. These results suggest that the plant extracts have some potential to be used as alternative antisickling therapy to hydroxyurea in SCD management.
Asunto(s)
Antidrepanocíticos/farmacología , Extractos Vegetales/farmacología , Alcaloides/química , Alcaloides/farmacología , Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/química , Cajanus/química , Carica/química , Eritrocitos/efectos de los fármacos , Flavonoides/química , Flavonoides/farmacología , Glicósidos/química , Glicósidos/farmacología , Humanos , Medicina Tradicional/métodos , Fitoquímicos/química , Fitoquímicos/farmacología , Extractos Vegetales/química , Hojas de la Planta/química , Saponinas/química , Saponinas/farmacología , Semillas/química , Taninos/química , Taninos/farmacología , Zanthoxylum/químicaRESUMEN
Hemoglobin (Hb) modifiers that stereospecifically inhibit sickle hemoglobin polymer formation and/or allosterically increase Hb affinity for oxygen have been shown to prevent the primary pathophysiology of sickle cell disease (SCD), specifically, Hb polymerization and red blood cell sickling. Several such compounds are currently being clinically studied for the treatment of SCD. Based on the previously reported non-covalent Hb binding characteristics of substituted aryloxyalkanoic acids that exhibited antisickling properties, we designed, synthesized and evaluated 18 new compounds (KAUS II series) for enhanced antisickling activities. Surprisingly, select test compounds showed no antisickling effects or promoted erythrocyte sickling. Additionally, the compounds showed no significant effect on Hb oxygen affinity (or in some cases, even decreased the affinity for oxygen). The X-ray structure of deoxygenated Hb in complex with a prototype compound, KAUS-23, revealed that the effector bound in the central water cavity of the protein, providing atomic level explanations for the observed functional and biological activities. Although the structural modification did not lead to the anticipated biological effects, the findings provide important direction for designing candidate antisickling agents, as well as a framework for novel Hb allosteric effectors that conversely, decrease the protein affinity for oxygen for potential therapeutic use for hypoxic- and/or ischemic-related diseases.
Asunto(s)
Antidrepanocíticos/química , Hemoglobinas/química , Regulación Alostérica/efectos de los fármacos , Antidrepanocíticos/síntesis química , Antidrepanocíticos/farmacología , Sitios de Unión , Ácido Clofíbrico/química , Ácido Clofíbrico/farmacología , Hemoglobinas/metabolismo , Modelos Moleculares , Conformación Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end-organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N-terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease-modifying agent in sickle cell patients.
Asunto(s)
Anemia de Células Falciformes/metabolismo , Antidrepanocíticos/farmacología , Supervivencia Celular/efectos de los fármacos , Eritrocitos Anormales/efectos de los fármacos , Eritrocitos Anormales/metabolismo , Hemoglobina Falciforme/metabolismo , Oxígeno/metabolismo , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/tratamiento farmacológico , Animales , Antidrepanocíticos/química , Antidrepanocíticos/farmacocinética , Análisis de los Gases de la Sangre , Modelos Animales de Enfermedad , Hemoglobina Falciforme/química , Humanos , Ratones , Agregación Patológica de Proteínas/tratamiento farmacológico , Agregación Patológica de Proteínas/metabolismo , Unión ProteicaRESUMEN
BACKGROUND: Scoparia dulcis Linn (Scrophulariaceae) together with other medicinal plants serve as antisickling remedies in Africa. This study was aimed at investigating the antisickling activity of the leaves of the plant as well as establishing the toxicological profile. METHOD: Chemical tests were employed in phytochemical investigations. Evaluation of the antisickling activity involved the inhibition of sodium metabisulphite-induced sickling of the HbSS red blood cells obtained from confirmed sickle cell patients who were not in crises. Concentrations of the crude extract and its fractions were tested with normal saline and p-hydroxybenzoic acid serving as controls. Acute toxicological evaluation was carried out in mice while 30-day assessment was done in rats. RESULTS: Phytochemical screening revealed the presence of alkaloids, tannins, flavonoids and saponins. Percentage sickling inhibitions of the aqueous methanol extracts of S. dulcis were significant all through the period of assay p < 0. 05 compared to normal saline, but not significant with PHBA. The fractions had less activity compared to the crude extracts. The LD 50 of the extract in mice was above 8000 mg/kg body weight when administered orally. Toxicological evaluations at 250 and 500 mg/kg showed mild congestion in virtually all the target organs. CONCLUSION: The antisickling results confirmed traditional usage of Scoparia dulcis in the management of Sickle cell disorders and a candidate for further investigations.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/administración & dosificación , Evaluación Preclínica de Medicamentos , Extractos Vegetales/administración & dosificación , Scoparia/química , Animales , Antidrepanocíticos/química , Antidrepanocíticos/toxicidad , Eritrocitos/efectos de los fármacos , Femenino , Humanos , Masculino , Ratones , Extractos Vegetales/química , Extractos Vegetales/toxicidad , Ratas , Ratas Wistar , Scoparia/toxicidadRESUMEN
Aromatic aldehydes and ethacrynic acid (ECA) exhibit antipolymerization properties that are beneficial for sickle cell disease therapy. Based on the ECA pharmacophore and its atomic interaction with hemoglobin, we designed and synthesized several compounds - designated as KAUS (imidazolylacryloyl derivatives) - that we hypothesized would bind covalently to ßCys93 of hemoglobin and inhibit sickling. The compounds surprisingly showed weak allosteric and antisickling properties. X-ray studies of hemoglobin in complex with representative KAUS compounds revealed an unanticipated mode of Michael addition between the ß-unsaturated carbon and the N-terminal αVal1 nitrogen at the α-cleft of hemoglobin, with no observable interaction with ßCys93. Interestingly, the compounds exhibited almost no reactivity with the free amino acids, L-Val, L-His and L-Lys, but showed some reactivity with both glutathione and L-Cys. Our findings provide a molecular level explanation for the compounds biological activities and an important framework for targeted modifications that would yield novel potent antisickling agents.
Asunto(s)
Acrilatos/farmacología , Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/farmacología , Hemoglobina Falciforme/antagonistas & inhibidores , Imidazoles/farmacología , Acrilatos/síntesis química , Acrilatos/química , Anemia de Células Falciformes/patología , Animales , Antidrepanocíticos/síntesis química , Antidrepanocíticos/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hemoglobina Falciforme/química , Humanos , Imidazoles/síntesis química , Imidazoles/química , Ratones , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
This article presents a study of vanillin encapsulation inside multilamellar liposomes, with emphasis on the evaluation of antioxidant activity, the hemolytic effect, and the antisickling properties of these products. Egg phosphatidylcholine-cholesterol and egg phosphatidylcholine-cholesterol-1-O-decylglycerol liposomes were prepared by mechanical dispersion, all with vanillin included. Vesicles were characterized by determination of encapsulation efficiency and vanillin retention capacity. Antioxidant activity was determined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. The hemolytic effect of liposomes was also evaluated by spectrophotometry, as well as the antisickling activity by the Huck test using optical microscopy. Results showed that the lipid composition of liposomes did not significantly affect the encapsulation efficiency. Stable vesicles were obtained with a high retention percentage of vanillin. Liposomes exhibited a high capture of the DPPH radical compared to free vanillin and 1-O-decylglycerol (C10) in solution. Vesicles caused no significant hemolisys in normal erythrocytes, nor in those coming from patients with sickle cell anemia. Vanillin encapsulated in liposomes retained its antisickling activity, with a greater effect for C10-containing vesicles. Our results show that vanillin encapsulation in liposomes is a way to enhance the pharmacologic properties of this molecule using a suitable vehicle.
Asunto(s)
Antioxidantes/farmacología , Antidrepanocíticos/farmacología , Benzaldehídos/farmacología , Extractos Vegetales/farmacología , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/tratamiento farmacológico , Antioxidantes/química , Antidrepanocíticos/química , Benzaldehídos/química , Química Farmacéutica , Portadores de Fármacos/química , Composición de Medicamentos , Eritrocitos/efectos de los fármacos , Humanos , Liposomas/química , Extractos Vegetales/química , Vanilla/químicaRESUMEN
In this study, both experimental and theoretical vibrational spectra of template (hydroxyurea, HU), monomer (N-(4,6-bisacryloyl amino-[1,3,5] triazine-2-yl-)-acryl amide, TAT), and HU-TAT complexes were compared and these were respectively found to be in good agreement. Binding energies of HU, when complexed with different monomers, were computed using second order Moller Plesset theory (MP2) at 6-311++G(d,p) level both in the gas as well as solution phases. HU is an antineoplastic agent extensively being used in the treatment of polycythaemia Vera and thrombocythemia. It is also used to reduce the frequency of painful attacks in sickle cell anemia. It has antiretroviral property in disease like AIDS. All spectral characterizations were made using Density Functional Theory (DFT) at B3LYP employing 6-31+g(2d,2p) basis set. The theoretical values for (13)C and (1)H NMR chemical shifts were found to be in accordance with the corresponding experimental values. Of all different monomers studied for the synthesis of molecularly imprinted polymer (MIP) systems, the monomer TAT (2 mol) was typically found to have a best binding score requisite for complexation with HU (1 mol) at the ground state.
Asunto(s)
Acrilamida/química , Antineoplásicos/química , Antidrepanocíticos/química , Hidroxiurea/química , Impresión Molecular/métodos , Polímeros/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Teoría Cuántica , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman , Triazinas/químicaRESUMEN
Vanillin has previously been studied clinically as an antisickling agent to treat sickle-cell disease. In vitro investigations with pyridyl derivatives of vanillin, including INN-312 and INN-298, showed as much as a 90-fold increase in antisickling activity compared with vanillin. The compounds preferentially bind to and modify sickle hemoglobin (Hb S) to increase the affinity of Hb for oxygen. INN-312 also led to a considerable increase in the solubility of deoxygenated Hb S under completely deoxygenated conditions. Crystallographic studies of normal human Hb with INN-312 and INN-298 showed that the compounds form Schiff-base adducts with the N-terminus of the α-subunits to constrain the liganded (or relaxed-state) Hb conformation relative to the unliganded (or tense-state) Hb conformation. Interestingly, while INN-298 binds and directs its meta-positioned pyridine-methoxy moiety (relative to the aldehyde moiety) further down the central water cavity of the protein, that of INN-312, which is ortho to the aldehyde, extends towards the surface of the protein. These studies suggest that these compounds may act to prevent sickling of SS cells by increasing the fraction of the soluble high-affinity Hb S and/or by stereospecific inhibition of deoxygenated Hb S polymerization.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/química , Benzaldehídos/química , Hemoglobina Falciforme/química , Piridinas/química , Anemia de Células Falciformes/metabolismo , Antidrepanocíticos/farmacología , Benzaldehídos/metabolismo , Benzaldehídos/uso terapéutico , Cristalización , Cristalografía por Rayos X , Hemoglobina Falciforme/metabolismo , Humanos , Oxígeno/química , Oxígeno/metabolismo , Unión Proteica/efectos de los fármacos , Conformación Proteica/efectos de los fármacos , Piridinas/metabolismo , Piridinas/uso terapéutico , Bases de Schiff/química , Solubilidad/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A novel series of thalidomide derivatives (4a-f) designed by molecular hybridization were synthesized and evaluated in vitro and in vivo for their potential use in the oral treatment of sickle cell disease symptoms. Compounds 4a-f demonstrated analgesic, anti-inflammatory, and NO-donor properties. Compounds 4c and 4d were considered promising candidate drugs and were further evaluated in transgenic sickle cell mice to determine their capacity to reduce the levels of the proinflammatory cytokine tumor necrosis factor α (TNFα). Unlike hydroxyurea, the compounds reduced the concentrations of TNFα to levels similar to those induced with the control dexamethasone (300 µmol/kg). These compounds are novel lead drug candidates with multiple beneficial actions in the treatment of sickle cell disease symptoms and offer an alternative to hydroxyurea treatment.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/síntesis química , Antidrepanocíticos/farmacología , Diseño de Fármacos , Ácido Acético , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/farmacología , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/metabolismo , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antidrepanocíticos/química , Capsaicina , Cólico/inducido químicamente , Cólico/metabolismo , Cólico/prevención & control , Oído/patología , Edema/inducido químicamente , Edema/metabolismo , Edema/prevención & control , Femenino , Masculino , Ratones , Ratones Transgénicos , Modelos Químicos , Estructura Molecular , Peritonitis/inducido químicamente , Peritonitis/metabolismo , Peritonitis/prevención & control , Talidomida/síntesis química , Talidomida/química , Talidomida/farmacología , Tioglicolatos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Sickle Cell Disease (SCD) is one of the most prevalent hematological diseases in the world. SCD is a genetic disease characterized by punctual mutation that basis on the exchange of glutamic acid to valine in a beta chain of hemoglobin. In deoxygenated state, the interaction among the beta chains leads to hemoglobin polymerization carrying out to deformation of cytoskeleton structure of red blood cells to a sickle shape. Currently, the treatment is performed with the antineoplasic drug hydroxyurea. This review summarizes current knowledge about possible targets and the approaches to discover new compounds to treat the SCD symptoms. Drug design based on therapeutical application and molecular modifications strategies will be discussed.