RESUMEN
Drug leads with a high Fsp3 index are more likely to possess desirable properties for progression in the drug development pipeline. This paper describes the development of an efficient two-step protocol to completely diastereoselectively access a diethanolamine (DEA) boronate ester derivative of monosaccharide d-galactose from the starting material 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose. This intermediate, in turn, is used to access 3-boronic-3deoxy-d-galactose for boron neutron capture therapy (BNCT) applications. The hydroboration/borane trapping protocol was robustly optimized with BH3.THF in 1,4-dioxane, followed by in-situ conversion of the inorganic borane intermediate to the organic boron product by the addition of DEA. This second step occurs instantaneously, with the immediate formation of a white precipitate. This protocol allows expedited and greener access to a new class of BNCT agents with an Fsp3 index = 1 and a desirable toxicity profile. Furthermore, presented is the first detailed NMR analysis of the borylated free monosaccharide target compound during the processes of mutarotation and borarotation.
Asunto(s)
Boranos , Terapia por Captura de Neutrón de Boro , Neoplasias , Humanos , Monosacáridos , Galactosa , Boro/química , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias/tratamiento farmacológico , Compuestos de Boro/farmacología , Compuestos de Boro/uso terapéuticoRESUMEN
Tetrachlorinated phthalimide analogues bearing a boron-pinacolate ester group were synthesised via two synthetic routes and evaluated in their glycosidase modulating and anticancer properties, with a view to use them in boron neutron capture therapy (BNCT), a promising radiation type for cancer, as this therapy does little damage to biological tissue. An unexpected decarbonylation/decarboxylation to five 2,3,4,5-tetrachlorobenzamides was observed and confirmed by X-ray crystallography studies, thus, giving access to a family of borylated 2,3,4,5-tetrachlorobenzamides. Biological evaluation showed the benzamide drugs to possess good to weak potencies (74.7-870 µM) in the inhibition of glycosidases, and to have good to moderate selectivity in the inhibition of a panel of 18 glycosidases. Furthermore, in the inhibition of selected glycosidases, there is a core subset of three animal glycosidases, which is always inhibited (rat intestinal maltase α-glucosidase, bovine liver ß-glucosidase and ß-galactosidase). This could indicate the involvement of the boron atom in the binding. These glycosidases are targeted for the management of diabetes, viral infections (via a broad-spectrum approach) and lysosomal storage disorders. Assays against cancer cell lines revealed potency in growth inhibition for three molecules, and selectivity for one of these molecules, with the growth of the normal cell line MCF10A not being affected by this compound. One of these molecules showed both potency and selectivity; thus, it is a candidate for further study in this area. This paper provides numerous novel aspects, including expedited access to borylated 2,3,4,5-tetrachlorophthalimides and to 2,3,4,5-tetrachlorobenzamides. The latter constitutes a novel family of glycosidase modulating drugs. Furthermore, a greener synthetic access to such structures is described.
Asunto(s)
Terapia por Captura de Neutrón de Boro , Neoplasias , Animales , Boro/química , Boro/farmacología , Compuestos de Boro/farmacología , Bovinos , Glicósido Hidrolasas , RatasRESUMEN
This review covers the literature in the past 15 years on glycosidase inhibitors lacking a basic nitrogen (for example iminosugars/azasugars) with a focus on natural terpenoids, and mono- and polycyclic aromatic hydrocarbons. From quite diverse structures, insight into inhibitor structural features that may be applicable to optimisation of all glycosidase inhibitors including iminosugars are identified.
Asunto(s)
Glicósido Hidrolasas , Iminoazúcares , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Iminoazúcares/química , Iminoazúcares/farmacologíaRESUMEN
A glucose-based vector for targeting cancer cells conjugated to a tris(methylpyridyl)amine (tpa) ligand to generate targeted chaperone and caging complexes for active anticancer agents is described. The ligand, tpa(CONHPEGglucose)1, inhibits hexokinase, suggesting that it will be phosphorylated in the cell. A Co(III) complex incorporating this ligand and coumarin-343 hydroximate (C343ha), [Co(C343ha){tpa(CONHPEGglucose)1}]Cl, is shown to exhibit glucose-dependent cellular accumulation in DLD-1 colon cancer cells. Cellular accumulation of [Co(C343ha){tpa(CONHPEGglucose)1}]+ is slower than for the glucose null and glucosamine analogues, and the glucose complex also exhibits a lower ability to inhibit antiproliferative activity. Distributions of cobalt (X-ray fluorescence) and C343ha (visible light fluorescence) in DLD-1 cancer cell spheroids are consistent with uptake of [Co(C343ha){tpa(CONHPEGglucose)1}]+ by rapidly dividing cells, followed by release and efflux of C343ha and trapping of the Co{tpa(CONHPEGglucose)1} moiety. The Co{tpa(CONHPEGglucose)1} moiety is shown to have potential for the caged and targeted delivery of highly toxic anticancer agents.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Efecto Warburg en Oncología/efectos de los fármacos , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cobalto/química , Complejos de Coordinación/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Hexoquinasa/antagonistas & inhibidores , Humanos , Esferoides Celulares/efectos de los fármacosRESUMEN
Short syntheses to high Fsp 3 index natural-product analogues such as imino-sugars are of paramount importance in the investigation of their biological activities and reducing the use of protecting groups is an advantageous synthetic strategy. An iso-propyl-idene group was employed towards the synthesis of seven-membered ring imino-sugars and the title compound, C9H15N3O5, was crystallized as an inter-mediate, in which the THF ring is twisted and the dioxolane ring adopts an envelope conformation: the dihedral angle between the rings is 67.50â (13)°. In the crystal, the hydroxyl groups participate in O-Hâ¯(O,O) and O-Hâ¯N hydrogen-bonding inter-actions, which generate chains of mol-ecules propagating parallel to the a-axis direction. There is a notable non-classical C-Hâ¯O hydrogen bond, which cross-links the [100] chains into (001) sheets.
RESUMEN
Ionic liquids (ILs) have advantageous physical properties, which resulted in a rapid growth of research in this area in the past 15 years. One of the biggest challenges preventing the widespread use of ILs is the cost of production due to complex synthetic routes and/or expensive starting materials. Keeping in mind these industrial needs for scale-up and the desirable properties for applications in the lubrification area, here, we report the design and synthesis of four novel series of hydrophobic room-temperature ILs (RTILs) achieved from cheap and commercially available starting materials, namely, silicon-based, imidazolium-based, phosphonium-based, and monomer imidazolium-based. These syntheses were developed as expedited chemistry protocols and possess a greener synthetic profile compared to previously reported ILs of similar structures. All the RTILs were characterized by 1D NMR (1H NMR, 13C NMR, 31P NMR, 19F NMR, and 11B NMR) and 2D NMR (COSY, HSQC, and HMBC) analyses, high-resolution mass spectrometry, and chemical tests (primarily the silver nitrate test). Preliminary thermal analysis tests by thermogravimetric analysis show all novel RTILs display remarkably high thermal stabilities (386-474 °C). Differential scanning calorimetry data show low glass transitions ranging from -36 to -72 °C, which suggests good free volume and ion mobility.
RESUMEN
Glycoconjugation to target the Warburg effect provides the potential to enhance selective uptake of anticancer or imaging agents by cancer cells. A Warburg effect targeting group, rationally designed to facilitate uptake by glucose transporters and promote cellular accumulation due to phosphorylation by hexokinase (HK), has been synthesised. This targeting group, the C2 modified glucose analogue 2-(2-[2-(2-aminoethoxy)ethoxy]ethoxy)-D-glucose, has been conjugated to the fluorophore nitrobenzoxadiazole to evaluate its effect on uptake and accumulation in cancer cells. The targeting vector has demonstrated inhibition of glucose phosphorylation by HK, indicating its interaction with the enzyme and thereby confirming the potential to facilitate an intracellular trapping mechanism for compounds it is conjugated with. The cellular uptake of the fluorescent analogue is dependent on the glucose concentration and is so to a greater extent than is that of the widely used fluorescent glucose analogue, 2-NBDG. It also demonstrates selective uptake in the hypoxic regions of 3D spheroid tumour models whereas 2-NBDG is distributed primarily through the normoxic regions of the spheroid. The increased selectivity is consistent with the blocking of alternative uptake pathways.
Asunto(s)
4-Cloro-7-nitrobenzofurazano/análogos & derivados , Desoxiglucosa/análogos & derivados , Sistemas de Liberación de Medicamentos , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Glucosa , Hexoquinasa/metabolismo , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Neoplasias , 4-Cloro-7-nitrobenzofurazano/farmacocinética , 4-Cloro-7-nitrobenzofurazano/farmacología , Hipoxia de la Célula , Línea Celular Tumoral , Desoxiglucosa/farmacocinética , Desoxiglucosa/farmacología , Glucosa/farmacocinética , Glucosa/farmacología , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
Six new organotin(IV) compounds of Schiff bases derived from S-R-dithiocarbazate [R = benzyl (B), 2- or 4-methylbenzyl (2M and 4M, respectively)] condensed with 2-hydroxy-3-methoxybenzaldehyde (oVa) were synthesised and characterised by elemental analysis, various spectroscopic techniques including infrared, UV-vis, multinuclear (¹H, 13C, 119Sn) NMR and mass spectrometry, and single crystal X-ray diffraction. The organotin(IV) compounds were synthesised from the reaction of Ph2SnCl2 or Me2SnCl2 with the Schiff bases (S2MoVaH/S4MoVaH/SBoVaH) to form a total of six new organotin(IV) compounds that had a general formula of [R2Sn(L)] (where L = Schiff base; R = Ph or Me). The molecular geometries of Me2Sn(S2MoVa), Me2Sn(S4MoVa) and Me2Sn(SBoVa) were established by X-ray crystallography and verified using density functional theory calculations. Interestingly, each experimental structure contained two independent but chemically similar molecules in the crystallographic asymmetric unit. The coordination geometry for each molecule was defined by thiolate-sulphur, phenoxide-oxygen and imine-nitrogen atoms derived from a dinegative, tridentate dithiocarbazate ligand with the remaining positions occupied by the methyl-carbon atoms of the organo groups. In each case, the resulting five-coordinate C2NOS geometry was almost exactly intermediate between ideal trigonal-bipyramidal and square-pyramidal geometries. The cytotoxic activities of the Schiff bases and organotin(IV) compounds were investigated against EJ-28 and RT-112 (bladder), HT29 (colon), U87 and SJ-G2 (glioblastoma), MCF-7 (breast) A2780 (ovarian), H460 (lung), A431 (skin), DU145 (prostate), BE2-C (neuroblastoma) and MIA (pancreatic) cancer cell lines and one normal breast cell line (MCF-10A). Diphenyltin(IV) compounds exhibited greater potency than either the Schiff bases or the respective dimethyltin(IV) compounds. Mechanistic studies on the action of these compounds against bladder cancer cells revealed that they induced the production of reactive oxygen species (ROS). The bladder cancer cells were apoptotic after 24 h post-treatment with the diphenyltin(IV) compounds. The interactions of the organotin(IV) compounds with calf thymus DNA (CT-DNA) were experimentally explored using UV-vis absorption spectroscopy. This study revealed that the organotin(IV) compounds have strong DNA binding affinity, verified via molecular docking simulations, which suggests that these organotin(IV) compounds interact with DNA via groove-binding interactions.
Asunto(s)
Benzaldehídos/síntesis química , Benzaldehídos/farmacología , Simulación por Computador , Compuestos Orgánicos de Estaño/síntesis química , Compuestos Orgánicos de Estaño/farmacología , Bases de Schiff/síntesis química , Bases de Schiff/farmacología , Benzaldehídos/química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Cristalografía por Rayos X , ADN/metabolismo , Humanos , Cinética , Conformación Molecular , Simulación del Acoplamiento Molecular , Compuestos Orgánicos de Estaño/química , Especies Reactivas de Oxígeno/metabolismo , Bases de Schiff/químicaRESUMEN
Amidine synthesis by amine addition to nitriles normally requires high temperatures or harsh catalysts. Here, we report that boronate esters can facilitate amidination of proximal amines with moderate heating. With amidines present in a number of drugs and the synthetic handle provided by the boron, this chemistry should find useful applications.
RESUMEN
The effect of different leaving groups on the substitution versus elimination outcomes with C-5 d-glucose derivatives was investigated. The stereochemical configurations of 3-O-benzyl-1,2-O-iso-propyl-idene-5-O-methane-sulfonyl-6-O-tri-phenyl-methyl-α-d-gluco-furan-ose, C36H38O8S (3) [systematic name: 1-[(3aR,5R,6S,6aR)-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl)-2-(trit-yloxy)ethyl methane-sulfonate], a stable inter-mediate, and 5-azido-3-O-benzyl-5-de-oxy-1,2-O-iso-propyl-idene-6-O-tri-phenyl-methyl-ß-l-ido-furan-ose, C35H35N3O5 (4) [systematic name: (3aR,5S,6S,6aR)-5-[1-azido-2-(trit-yloxy)eth-yl]-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxole], a substitution product, were examined and the inversion of configuration for the azido group on C-5 in 4 was confirmed. The absolute structures of the mol-ecules in the crystals of both compounds were confirmed by resonant scattering. In the crystal of 3, neighbouring mol-ecules are linked by C-Hâ¯O hydrogen bonds, forming chains along the b-axis direction. The chains are linked by C-Hâ¯π inter-actions, forming layers parallel to the ab plane. In the crystal of 4, mol-ecules are also linked by C-Hâ¯O hydrogen bonds, forming this time helices along the a-axis direction. The helices are linked by a number of C-Hâ¯π inter-actions, forming a supra-molecular framework.
RESUMEN
3,4,5-Trihydroxypiperidines belong to the family of 1,5-dideoxy-1,5-iminosugar natural products and are structural analogues of pentose monosaccharides in the pyranose form. The biological activities of these apparently structurally simple molecules and their N- and O-alkylated and -arylated derivatives are no less remarkable than their C-6 hydroxymethyl counterparts of the hexoses (such as 1-deoxynojirimycin, DNJ). Their biological profiles indicate that the hydroxymethyl branch is crucial to neither potency nor selectivity, with O-alkylation demonstrated to produce exquisite selectivity extending beyond glycosidase inhibition, to immunosuppressant and antibacterial activities.
Asunto(s)
Productos Biológicos/química , Piperidinas/química , 1-Desoxinojirimicina/química , Animales , Antivirales/química , Antivirales/farmacología , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Glicósido Hidrolasas/antagonistas & inhibidores , Glicósido Hidrolasas/metabolismo , Rechazo de Injerto/prevención & control , VIH-1/efectos de los fármacos , Monosacáridos/química , Piperidinas/farmacología , Piperidinas/uso terapéuticoRESUMEN
Glycosidases have important anti-cancer, anti-viral and anti-diabetic properties. This review covers the literature in the past 15 years since our initial review in this journal on "neutral" glycosidase inhibitors lacking a basic nitrogen found in iminosugars and azasugars or inhibitors that are neutral by virtue of being "charge-balanced" (zwitterionic). These structurally diverse inhibitors include lactones, lactams, epoxides such as cyclophellitol, and sulfonium ion derivatives of the natural product salacinol. Synthetic efforts toward cyclophillitol, salicinol and derivatives are also highlighted. Importantly, certain metals can inhibit glycosidases and care must be taken to remove residual catalysts from synthetic material to be tested against these enzymes.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Glicósido Hidrolasas/metabolismo , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
BACKGROUND AND PURPOSE: Cystic fibrosis (CF) is a debilitating disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for a Cl-/HCO3 - channel. F508del, the most common CF-associated mutation, causes both gating and biogenesis defects in the CFTR protein. This paper describes the optimization of two fluorescence assays, capable of measuring CFTR function and cellular localization, and their use in a pilot drug screen. EXPERIMENTAL APPROACH: HEK293 cells expressing YFP-F508del-CFTR, in which halide sensitive YFP is tagged to the N-terminal of CFTR, were used to screen a small library of compounds based on the VX-770 scaffold. Cells expressing F508del-CFTR-pHTomato, in which a pH sensor is tagged to the fourth extracellular loop of CFTR, were used to measure CFTR plasma membrane exposure following chronic treatment with the novel potentiators. KEY RESULTS: Active compounds with efficacy ~50% of VX-770, micromolar potency, and structurally distinct from VX-770 were identified in the screen. The F508del-CFTR-pHTomato assay suggests that the hit compound MS131A, unlike VX-770, does not decrease membrane exposure of F508del-CFTR. CONCLUSIONS AND IMPLICATIONS: Most known potentiators have a negative influence on F508del-CFTR biogenesis/stability, which means membrane exposure needs to be monitored early during the development of drugs targeting CFTR. The combined use of the two fluorescence assays described here provides a useful tool for the identification of improved potentiators and correctors. The assays could also prove useful for basic scientific investigations on F508del-CFTR, and other CF-causing mutations.
Asunto(s)
Aminofenoles/análisis , Aminofenoles/farmacología , Proteínas Bacterianas/análisis , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Fluorescencia , Proteínas Luminiscentes/análisis , Quinolonas/análisis , Quinolonas/farmacología , Bibliotecas de Moléculas Pequeñas/análisis , Bibliotecas de Moléculas Pequeñas/farmacología , Aminofenoles/síntesis química , Aminofenoles/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Células HEK293 , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Estructura Molecular , Quinolonas/síntesis química , Quinolonas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Ciclofilinas/antagonistas & inhibidores , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Esclerosis Múltiple/prevención & control , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Compuestos de Quinolinio/uso terapéutico , Sustitución de Aminoácidos , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/inmunología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Peptidil-Prolil Isomerasa F , Ciclofilinas/genética , Ciclofilinas/metabolismo , Ciclosporinas/efectos adversos , Ciclosporinas/síntesis química , Ciclosporinas/farmacología , Ciclosporinas/uso terapéutico , Células Hep G2 , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos , Ratones Noqueados , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Mutación , Neuronas/inmunología , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacología , Péptidos Cíclicos/efectos adversos , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/uso terapéutico , Compuestos de Quinolinio/efectos adversos , Compuestos de Quinolinio/síntesis química , Compuestos de Quinolinio/farmacología , Distribución Aleatoria , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/patologíaRESUMEN
There has been an increasing body of evidence that flow hydrogenation enhances reduction outcomes across a wide range of synthetic transformations. Moreover flow reactors enhance laboratory safety with pyrophoric catalysts contained in sealed cartridges and hydrogen generated in situ from water. This mini-review focuses on recent applications of flow chemistry to mediate nitro, imine, nitrile, amide, azide, and azo reductions. Methodologies to effect de-aromatisation, hydrodehalogenation, in addition to olefin, alkyne, carbonyl, and benzyl reductions are also examined. Further, protocols to effect chemoselective reductions and enantioselective reductions are highlighted. Together these applications demonstrate the numerous advantages of performing hydrogenation under flow conditions which include enhanced reaction throughput, yields, simplified workup, and the potential applicability to multistep and cascade synthetic protocols.
Asunto(s)
Química Orgánica/métodos , Catálisis , Hidrogenación , Compuestos Orgánicos/química , EstereoisomerismoRESUMEN
The endothelium plays a fundamental role in maintaining vascular homeostasis by releasing factors that regulate local blood flow, systemic blood pressure, and the reactivity of leukocytes and platelets. Accordingly, endothelial dysfunction underpins many cardiovascular diseases, including hypertension, myocardial infarction, and stroke. Herein, we evaluated mice with endothelial-specific deletion of Nppc, which encodes C-type natriuretic peptide (CNP), and determined that this mediator is essential for multiple aspects of vascular regulation. Specifically, disruption of CNP leads to endothelial dysfunction, hypertension, atherogenesis, and aneurysm. Moreover, we identified natriuretic peptide receptor-C (NPR-C) as the cognate receptor that primarily underlies CNP-dependent vasoprotective functions and developed small-molecule NPR-C agonists to target this pathway. Administration of NPR-C agonists promotes a vasorelaxation of isolated resistance arteries and a reduction in blood pressure in wild-type animals that is diminished in mice lacking NPR-C. This work provides a mechanistic explanation for genome-wide association studies that have linked the NPR-C (Npr3) locus with hypertension by demonstrating the importance of CNP/NPR-C signaling in preserving vascular homoeostasis. Furthermore, these results suggest that the CNP/NPR-C pathway has potential as a disease-modifying therapeutic target for cardiovascular disorders.
Asunto(s)
Endotelio Vascular/fisiología , Homeostasis , Péptido Natriurético Tipo-C/fisiología , Animales , Aneurisma de la Aorta/etiología , Aterosclerosis/etiología , Plaquetas/fisiología , Presión Sanguínea , Calcio/metabolismo , Femenino , Leucocitos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/metabolismo , Ratas , Vasodilatación/efectos de los fármacosRESUMEN
IN THE TITLE COMPOUND (SYSTEMATIC NAME: {(3aS,5S,6R,6aS)-3a-[(benz-yloxy)meth-yl]-6-hy-droxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl}methyl 4-methyl-benzene-sulfonate), C23H28O8S, the absolute structure and relative stereochemistry of the four chiral centres have been established by X-ray crystallography, with the absolute configuration inferred from the use of l-sorbose as the starting material. The central furan-ose ring adopts a slightly twisted envelope conformation (with the C atom bearing the methyl-benzene-sulfonate substituent as the flap) from which three substituents depart pseudo-axially (-CH2-O-benzyl, -OH and one acetonide O atom) and two substituents pseudo-equatorially (-CH2-O-tosyl and second acetonide O atom). The dioxalane ring is in a flattened envelope conformation with the fused CH C atom as the flap. In the crystal, mol-ecules pack in columns along [010] linked by O-Hâ¯O hydrogen bonds involving the furan-ose hy-droxy group and furan-ose ether O atom.
RESUMEN
This compendium focuses on functionalised sugar amino acids (SAAs) and their 3- to 6-membered nitrogen heterocyclic and carbocyclic analogues. The main benefit of using SAAs and their related nitrogen and carbon congeners in the production of peptidomimetics and glycomimetics is that their properties can be readily altered via modification of their ring size, chemical manipulation of their numerous functional groups and fine-tuning of the stereochemical arrangement of their ring substituents. These building blocks provide access to hydrophilic and hydrophobic peptide isosteres whose physical properties allow entry to a region of chemotherapeutic space which is still under-explored by medicinal chemists. These building blocks are also important in providing amino acids whose inherent conformational bias leads to predisposition to secondary structure upon oligomerisation in relatively short sequences. These foldamers, particularly those containing ω-amino acids, provide an additional opportunity to expand access to the control of structures by artificial peptides. The synthesis and biological evaluation of these building blocks in glycomimetics and peptidomimetics systems keep expanding the reach of the glycosciences to the medical sciences, provide a greater outlook onto the wide range of cellular functions of saccharides and their derivatives involved and greater insight into the nature of oligosaccharide and protein folding.
Asunto(s)
Aminoácidos/química , Carbohidratos/química , Compuestos Heterocíclicos/química , Nitrógeno/química , Aminoácidos/síntesis química , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Estructura MolecularRESUMEN
The small molecule carrier class of biomolecule transporters, modeled on the third helix of the Antennapedia homeodomain, has previously been shown to transport active proteins into cells. Here, we show an improved synthetic route to small molecule carriers, including Molander chemistry using trifluoroborate salts to improve the yield of the Suzuki-Miyaura coupling step for the formation of the biphenyl backbone. The required boronic acids could be formed by the reaction of a 2-(dimethylamino)ethyl ether-modified aryl Grignard reagent with triisopropyl borate. The potential for the use of small molecule carriers as oligonucleotide-transporting agents was also explored by characterizing the interactions between small molecule carriers and siRNA. Molecular dynamics and NMR analysis indicated that the small molecule carrier guanidines are stabilized by π-cation interactions with the biphenyl system, thus not only increasing the basicity or pKa but also shielding the charge. The binding affinities of various small molecule carriers for siRNA were investigated using isothermal calorimetry and gel shift assays. Small molecule carrier-mediated siRNA delivery to cultured fibroblasts is demonstrated, showing that small molecule carriers possess the ability to transport functional siRNA into cells. Knockdown of Cdc7 kinase, a target for cancer, is achieved.
Asunto(s)
ARN Interferente Pequeño/química , Bibliotecas de Moléculas Pequeñas/química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Guanidina/química , Humanos , Cinética , Microscopía Confocal , Simulación de Dinámica Molecular , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis químicaRESUMEN
Mitochondrial CyP-D (cyclophilin-D) catalyses formation of the PT (permeability transition) pore, a key lesion in the pathogenesis of I/R (ischaemia/reperfusion) injury. There is evidence [Malouitre, Dube, Selwood and Crompton (2010) Biochem. J. 425, 137-148] that cytoprotection by the CyP inhibitor CsA (cyclosporin A) is improved by selective targeting to mitochondria. To investigate this further, we have developed an improved mtCsA (mitochondrial-targeted CsA) by modifying the spacer linking the CsA to the TPP+ (triphenylphosphonium) (mitochondrial-targeting) cation. The new mtCsA exhibits an 18-fold increase in binding affinity for CyP-D over the prototype and a 12-fold increase in potency of inhibition of the PT in isolated mitochondria, owing to a marked decrease in non-specific binding. The cytoprotective capacity was assessed in isolated rat cardiomyocytes subjected to transient glucose and oxygen deprivation (pseudo-I/R). The new mtCsA was maximally effective at lower concentrations than CsA (3-15 nM compared with 50-100 nM) and yielded improved cytoprotection for up to 3 h following the pseudo-ischaemic insult (near complete compared with 40%). These data indicate the potential value of selective CyP-D inhibition in cytoprotection.