ABSTRACT
Polycationic oligo(chiral bicyclic guanidines) constitute useful non-peptidic penetrating agents for cell uptake and protein surface recognition. We report herein improved and selective procedures for the preparation of oligoguanidinium scaffolds linked through thioether bonds, with similar or different groups and functions at both ends of the chain. Two synthetic strategies were developed to obtain these compounds in relatively good yields from a common thioacetate precursor: generation of a disulfide intermediate or thiolate formation. Thus, tetraguanidinium intermediates 8 and 22 are best synthesized by the disulfide route, whereas hexamer 29, octamer 31, and trimer 37 arise from a combination of both the disulfide and the thioacetate routes. Finally, tetramer 28 can be readily obtained from either strategy.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/metabolism , Guanidine/chemistry , Guanidine/metabolism , Bridged Bicyclo Compounds/chemical synthesis , Cell Membrane Permeability , Chemistry Techniques, Synthetic , Disulfides/chemical synthesis , Disulfides/chemistry , Guanidine/chemical synthesis , HeLa Cells , Humans , Polyamines/chemical synthesis , Polyamines/chemistry , Polyamines/metabolism , Polyelectrolytes , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/chemistryABSTRACT
A useful strategy for cycloheptane annulations from oxo- and epoxyallylsilanes, prepared by silylcupration of allenes, has been developed, and their application to the stereoselective synthesis of 4-methylenecycloheptan-1-ols is of great potential in the construction of seven-membered ring natural products presented.
ABSTRACT
A simple solid-phase synthesis of thioether-linked chiral bicyclic guanidinium oligomers for cell internalization purposes has been developed. The approach is based on a Merrifield-like peptide synthesis on Rinkamide-p-methylbenzhydrylamine resin functionalized with Cys(methoxytrityl). A difunctionalized bicyclic guanidinium synthon, bearing both electrophile (O-mesyl) and protected nucleophile (S-methoxytrityl) group, is repeatedly grafted via a nucleophilic substitution. The sequence requires removal of methoxytrityl, reduction with 1,4-dithiothreitol to cleave any adventitious disulfides, coupling and capping with benzyl bromide. Moreover, Alloc protection of the alpha-amino group of the initial cysteine, provides a potential handle for cargo attachment after oligomer elongation to the desired internalizing agent and prior to cleaving it from the resin. Finally, a bicyclic guanidinium monomer containing an amino group and a carboxylic acid function has been evaluated as an alternative building block for novel amide-bridged oligomers or peptidomimetics.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Combinatorial Chemistry Techniques/methods , Guanidine/chemical synthesis , Sulfides/chemistry , Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/chemistry , Benzyl Compounds/chemical synthesis , Benzyl Compounds/chemistry , Bridged Bicyclo Compounds/chemistry , Combinatorial Chemistry Techniques/economics , Cysteine/chemical synthesis , Cysteine/chemistry , Dithiothreitol/chemical synthesis , Dithiothreitol/chemistry , Guanidine/chemistry , Stereoisomerism , Sulfides/chemical synthesisABSTRACT
Multivalency plays a pivotal role in biological recognition, particularly at protein-protein and protein-carbohydrate interaction sites. Scaffolds of diverse structure, flexibility, and valency are gaining increasing biomedical importance in the development of artificial multivalent ligands for these interfaces. Relevant examples range from small C(4) symmetric calix[4]arenes and porphyrin ligands, which may achieve nanomolar affinity for protein surfaces of pharmaceutical interest, to large-sized dendrimers that provide promising adherence-inhibition for toxins and other relevant lectins. In addition, highly flexible supramolecular platforms like rotaxanes and polymers have been proposed as challenging alternatives to more rigid designs. Finally, nanoparticles are being exploited for this aim as they present important advantages from the biological and synthetic points of view.
Subject(s)
Proteins/chemistry , Animals , Catalysis , Humans , Inorganic Chemicals/chemistry , Organic Chemicals/chemistry , Protein Binding , Proteins/metabolismABSTRACT
An emissive terbium complex has been conjugated to a C12 chain, Lys-Arg7, Arg7, a tetraguanidinium cation and human serum albumin; two-photon excitation at 720 nm facilitated microscopy studies revealing cell localisation profiles with the oligo-guanidinium conjugate localising in mitochondria but causing apoptotic cell death (IC(50)12 microM), the C12-amide complex giving rise to necrotic cell death in skin fibroblasts (IC50 8 microM) and the peptide conjugates and the methyl ester generating punctuate cytosolic intracellular distributions.
Subject(s)
Arginine/chemistry , Cell Compartmentation/drug effects , Guanidine/chemistry , Organometallic Compounds/chemistry , Terbium/chemistry , Animals , Apoptosis/drug effects , Dose-Response Relationship, Drug , Fibroblasts/chemistry , Fibroblasts/drug effects , Fibroblasts/metabolism , HeLa Cells , Humans , Ligands , Mice , Microscopy, Fluorescence/methods , Mitochondria/chemistry , Mitochondria/drug effects , Mitochondria/metabolism , Molecular Conformation , NIH 3T3 Cells , Organometallic Compounds/pharmacokinetics , Peptides/chemistry , Photons , Serum Albumin/chemistry , Skin/chemistry , Skin/cytology , StereoisomerismABSTRACT
[reaction: see text] Epoxyallylsilanes bearing the bulky tert-butyldiphenylsilyl group undergo an uncommon tandem rearrangement-cyclization process upon treatment with Lewis acids. Two pathways for the carbonyl ene reaction are observed: one leading to allylsilane-cyclohexanols when the epoxyallylsilane (28-31) is nonsubstituted, 2-, or 4-monosubstituted and other leading to vinylsilane-cyclohexanols when the epoxyallylsilane (24-27) is 2,4-disubstituted or trisubstituted. An explanation for the observed regio- and stereoselectivity is advanced and a reliable mechanism proposed.
ABSTRACT
A novel highly stereoselective spiro-cyclopropanation reaction from oxoallylsilanes is described. Oxoallylsilanes are readily obtained by silylcupration of allene followed by conjugate addition to enones. The former oxoallylsilanes undergo a tandem cyclization-cyclopropanation reaction when treated with CH2I2/Me3Al, leading to hydroxylated polycyclic systems bearing the spiro-cyclopropane moiety. The scope of the process is studied, and a feasible pathway is discussed.
Subject(s)
Cyclopropanes/chemical synthesis , Silanes/chemistry , Spiro Compounds/chemical synthesis , Biological Factors/chemical synthesis , Cyclization , Silanes/chemical synthesisABSTRACT
[reaction: see text]. A new route for the synthesis of epoxyallylsilanes bearing the phenyldimethylsilyl group is reported that involves silylcupration of allene, conjugate addition to enones, and sulfur-ylide-mediated epoxidation. The Lewis acid-catalyzed cyclization of these substrates is presented. The expected normal products derived from 5-exo and/or 6-endo attack are not observed; instead, methylenecyclohexanols resulting from a tandem rearrangement-cyclization process are formed.