ABSTRACT
Nucleosides represent a major chemotherapeutic class for treating cancer, however their limitations in terms of cellular uptake, nucleoside kinase-mediated activation and catabolism are well-documented. The monophosphate pro-nucleotides known as ProTides represents a powerful strategy for bypassing the dependence on active transport and nucleoside kinase-mediated activation. Herein, we report the structural tuning of BVdU ProTides. Forty six phosphoramidates were prepared and biologically evaluated against three different cancer cell lines; murine leukemia (L1210), human CD4+ T-lymphocyte (CEM) and human cervical carcinoma (HeLa). Twenty-fold potency enhancement compared to BVdU was achieved against L1210 cells. Interestingly, a number of ProTides showed low micromolar activity against CEM and HeLa cells compared to the inactive parent BVdU. The ProTides showed poor, if any measurable toxicity to non-tumourigenic human lung fibroblast cell cultures. Separation of four pairs of the diastereoisomeric mixtures and comparison of their spectral properties, biological activities and enzymatic activation rate is reported.
Subject(s)
Amides/chemistry , Amides/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Bromodeoxyuridine/analogs & derivatives , Phosphoric Acids/chemistry , Phosphoric Acids/pharmacology , Amides/metabolism , Amides/pharmacokinetics , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacokinetics , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Bromodeoxyuridine/chemistry , Bromodeoxyuridine/metabolism , Bromodeoxyuridine/pharmacokinetics , Bromodeoxyuridine/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Mice , Neoplasms/drug therapy , Phosphoric Acids/metabolism , Phosphoric Acids/pharmacokineticsABSTRACT
A supramolecular approach for modeling active sites of metallo-enzymes relies on the association of a metal ion bound to a tris(imidazole) core under the control of a cavity. One step further is the water-solubilization of the cavity-complex. Here, we describe the synthesis of a water-soluble bowl-ligand that has been successively achieved through an 11-step strategy from resorcinol. First insights into its coordination properties in water show that it readily binds Zn(II) at physiological pH and acts as a molecular receptor for the hydrophilic acetate guest ligand.
Subject(s)
Acetates/analysis , Biomimetic Materials/chemistry , Imidazoles/chemistry , Organometallic Compounds/chemistry , Water/chemistry , Zinc/chemistry , Biomimetic Materials/chemical synthesis , Hydrogen-Ion Concentration , Molecular Conformation , Organometallic Compounds/chemical synthesis , SolubilityABSTRACT
Modeling the mononuclear site of copper enzymes is important for a better understanding of the factors controlling the reactivity of the metal center. A major difficulty stems from the difficult control of the nuclearity while maintaining free sites open to coordination of exogenous ligands. A supramolecular approach consists in associating a hydrophobic cavity to a tripodal ligand that will define the coordination spheres as well as access to the metal ion. Here, we describe the synthesis of a bowl Cu(II) complex based on the resorcinarene scaffold. This study supplements a previous work on Cu(I) coordination. It provides a complete picture of the cavity-copper system in its two oxidation states. The first XRD structure of such a bowl complex was obtained, evidencing a 5-coordinate Cu(II) ion with the three imidazole donors bound to the metal (two in the base of the pyramid, one in the apical position) and with an acetate anion, completing the base of the pyramid, and deeply included in the bowl. Solution studies conducted by EPR and UV-vis absorption spectroscopies as well as cyclic voltammetry highlighted interaction with coordinating solvents, various carboxylates that can sit either in the endo or in the exo position depending on their size as well as possible stabilization of hydroxo species in a mononuclear state. A comparison of the binding and redox properties of the bowl complex with funnel complexes based on the calix[6]arene core further highlights the importance of supramolecular features defining the first, second, and third coordination sphere for control of the metal ion.
Subject(s)
Calixarenes/chemistry , Coordination Complexes/chemistry , Copper/chemistry , Phenylalanine/analogs & derivatives , Biocatalysis , Biomimetics , Calixarenes/chemical synthesis , Coordination Complexes/chemical synthesis , Crystallography, X-Ray , Models, Molecular , Oxidation-Reduction , Phenols/chemistry , Phenylalanine/chemical synthesis , Phenylalanine/chemistryABSTRACT
Superoxide reductase (SOR), a non-heme mononuclear iron protein that is involved in superoxide detoxification in microorganisms, can be used as an unprecedented model to study the mechanisms of O2 activation and of the formation of high-valent iron-oxo species in metalloenzymes. By using resonance Raman spectroscopy, it was shown that the mutation of two residues in the second coordination sphere of the SOR iron active site, K48 and I118, led to the formation of a high-valent iron-oxo species when the mutant proteins were reacted with H2O2. These data demonstrate that these residues in the second coordination sphere tightly control the evolution and the cleavage of the O-O bond of the ferric iron hydroperoxide intermediate that is formed in the SOR active site.
Subject(s)
Iron/chemistry , Oxidoreductases/chemistry , Spectrum Analysis, Raman/methods , Binding SitesABSTRACT
(D)-Glucosamine and other nutritional supplements have emerged as safe alternative therapies for osteoarthritis (OA), a chronic and degenerative articular joint disease. In our preceding paper, a series of novel O-6 phosphate N-acetyl (d)-glucosamine prodrugs aimed at improving the oral bioavailability of N-acetyl-(d)-glucosamine as its putative bioactive phosphate form were shown to have greater chondroprotective activity in vitro when compared to the parent agent. In order to extend the SAR studies, this work focuses on the O-3 and O-4 phosphate prodrugs of N-acetyl-(d)-glucosamine bearing a 4-methoxy phenyl group and different amino acid esters on the phosphate moiety. Among the compounds, the (l)-proline amino acid-containing prodrugs proved to be the most active of the series, more effective than the prior O-6 compounds, and well processed in chondrocytes in vitro. Data on human cartilage support the notion that these novel O-3 and O-4 regioisomers may represent novel promising leads for drug discovery for osteoarthritis.
Subject(s)
Acetylglucosamine/analogs & derivatives , Acetylglucosamine/chemical synthesis , Cartilage, Articular/drug effects , Organophosphorus Compounds/chemical synthesis , Osteoarthritis/drug therapy , Prodrugs/chemical synthesis , Acetylglucosamine/pharmacology , Aggrecans/metabolism , Animals , Cartilage, Articular/metabolism , Cattle , Chondrocytes/drug effects , Chondrocytes/metabolism , Drug Stability , Glycosaminoglycans/metabolism , Guinea Pigs , Half-Life , Humans , Organ Culture Techniques , Organophosphorus Compounds/pharmacology , Prodrugs/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A highly effective method for the introduction of a formyl group at the anomeric position of pyranosides was developed via enolisation of beta-C-D-glycopyranosylpropan-2-one using thermodynamic conditions then oxidative cleavage of the more substituted double bond. This sequence affords the desired aldehydes that are conveniently protected as aminals for purification and storage and easily regenerated using Dowex resin H+. In this paper, the syntheses of nine differently protected aldehydes derived from d-glucose, d-galactose, lactose and N-acetyl-d-glucosamine are presented. Our strategy proved to be very efficient in most cases excepted in the D-mannose series.