Labile Metabolites

The importance of ascertaining the possible presence of unstable metabolites at an early stage in the drug development process cannot be underestimated. Failure to detect labile metabolites could lead to costly delays to development. Very often, erratic or difficult to explain analytical or kinetic data provide clues to metabolite degradation, the most commonly encountered reaction being the conversion of a metabolite to parent drug. Examples of unstable glucuronide conjugates, N-oxides, alcohols and phenols abound in the literature. They are not easy to find, however, and have to be ‘mined’ by extensive searching. This report, by no means exhaustive, brings together the major examples according to substance class. Remedial action to avoid metabolite degradation is discussed, as well as a number of specific examples which cannot be categorised under the main substance classes.     

Fluorinated dendrimers

After pioneering works concerning the synthesis of dendrimers and dendrons possessing fluorine atoms in some part of their structure, recent advances are dedicated to the search for uses and applications of these highly branched compounds. Three major fields are concerned: catalysis, materials science and biology to a lesser extend.     

Stilbenoid dendrimers

The first five generations of the stilbenoid dendrimers 1(n) (n = 1-5) have been prepared by a combined coupled synthesis (between the generations of the dendrons 8-12) and convergent synthesis. Wittig-Horner reactions together with a protecting group technique yield monodisperse compounds of high constitutional and configurational purity. The solubility of the stiff molecules, which have primarily a disklike shape in the first and second generations and a cylindrical shape in the third, fourth, and fifth generations, is governed by the alkoxy chains that are attached to the peripheral benzene rings. The number of stilbene building blocks increases according to the formula 3(2(n)-1) from 3 in the first generation (n = 1) to 93 in the fifth generation (n = 5). Consequently, the molecular mass reaches 24,000 in 1(5)b which contains 144 hexyloxy chains. An exact measurement of the mass is provided by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. In solution, the stilbenoid dendrimers 1(n) exhibit a strong tendency to aggregate, which increases from generation to generation. In the pure state, columnar mesophases Col(hd) (1(1)b, 1(1)c, 1(2)b, and 1(2)c) and Col(ob) (1(2)b, 1(2)c) are formed; intramolecular steric hindrance prevents such ordered arrangements in higher generations 1(n) (n = 3, 4, 5).     

Depsipeptide dendrimers

The convergent synthesis of a new class of chiral dendrimers is described. Owing to their structural resemblance to depsipeptides they are called depsipeptide dendrimers. The ex-chiral pool synthesis starts from (R,R)-, (S,S)-, and meso-tartaric acid as branching units and dipeptides or tripeptides consisting of glycine, (L)-alanine, and (L)-leucine as chiral-spacer building blocks. The key intermediates for the convergent assembly of such depsipeptide dendrimers are the peptide-tartaric acid conjugates 13a,b, 19a,b, 25, and 27, which contain either an unprotected C terminus of the peptide chain (13 a,b, 25) or two unprotected hydroxy groups within the tartaric acid termini. Dendra up to the third-generation, by using different combinations of stereoisomeric building blocks, were synthesized and completely characterized. Since this construction principle of chiral depsipeptide dendrimers allows for a wide variation of the length, the primary structure of the peptide spacer, and the configuration of both the amino acid and the tartaric acid moieties, access to new combinatorial libraries is conceptually provided.     

Organocatalytic dendrimers

Dendrimers are a class of synthetic macromolecules that bridge the gap between polymers and small molecules. The dendritic structure provides both the possibility for compartmentalization of reagents as well as offering a multivalent surface, and they are in that respect similar to globular proteins. This perspective article reviews the growing field of organocatalysis with dendrimers and highlights the possibilities that are unattainable for small molecule catalysts.     

Self-assembled oligonucleotide-polyester dendrimers

A new approach to the controlled synthesis of multicomponent dendrimers is presented, in which three oligonucleotide-dendron conjugates were synthesized using solid phase techniques and hybridized to create a second generation polyester dendrimer with DNA as a core and bearing two types of peripheral functional groups.     

Organocatalysis with dendrimers

This review gives an overview of the use of dendrimers and dendrons as organocatalysts, i.e. as catalysts in the absence of any metal. A large variety of dendrimeric structures have already been used for such a purpose, varying in size (generation), type and location (core or surface) of the organocatalytic entities, and overall chemical composition. The main types of reactions catalyzed concern bond formation (in particular C-C bonds), bond cleavage (in particular of esters), reductions and oxidations. In many cases, good to excellent enantioselectivities have been observed, in some cases associated with a positive dendritic effect (better properties when the generation of the dendrimer increases). Due to their large size compared to products, the dendrimeric organocatalysts can be often recovered and reused several times.     

Peptide-functionalized polyphenylene dendrimers

This contribution describes the synthesis of polyphenylene dendrimers that are functionalized with up to 16 lysine residues or substituted with short peptide sequences composed of 5 lysine or glutamic acid repeats and a C- or N-terminal cysteine residue. Polyphenylene dendrimers were prepared via a sequence of Diels-Alder cycloaddition and deprotection reactions from cyclopentadienone building blocks. Single amino acids could be introduced on the periphery of the dendrimers by using amino acid substituted cyclopentadienones in the last Diels-Alder addition reaction. Alternatively, peptide sequences were attached via a chemoselective reaction, which involved the addition of the sulfhydryl group of a cysteine residue of an oligopeptide to a maleimide moiety present on the surface of the dendrimer. These amino acid and peptide functionalized dendrimers may be of interest as model compounds to study DNA complexation and condensation or as building blocks for the preparation of novel supramolecular architectures via layer-by-layer self-assembly.     

Labile clustering and its effects

A contour map of the minimum values for three-body rate constants and for equilibrium constants has been constructed for the initial three-body clustering of gas molecules to positive ions. The map was constructed from laboratory measurements of the clustering of gas molecules to alkali ions and consolidates into a readily useful form several recent measurements. Use of the map shows that labile clustering can be extremely important in laboratory experiments and in the earth's upper atmosphere.     

Collagen mimetic dendrimers

The synthesis of single-chain, scaffold (TRIS)- and dendrimer-assembled collagen mimetics (both Gly-Pro-Nleu and Gly-Nleu-Pro sequences) is reported. From the CD spectra and the thermal denaturation studies it can be readily seen that mimetics prepared from the Gly-Nleu-Pro sequence form more thermally stable triple helices than the Gly-Pro-Nleu sequence. Furthermore, the 162-residue collagen mimetic dendrimers exhibit enhanced triple helical stability compared to equivalent scaffold-terminated structures by a substantial increase in the melting temperature in H2O and 2:1 EG/H2O. The concentration dependence for the melting transition was measured which determined that the stabilization effect arises from the intramolecular clustering of the triple helical arrays about the core structure. This ensemble excludes solvent from the interior portion of the array which stabilizes the triple helical bundle.     

树形化合物的研究进展

本文介绍了一类高度支化、带有很多末端官能团的新的大分子化合物-树形物。在这类化合物合成中, 可以控制分子形状和分子量。文中还分类介绍了这类化合物的合成方法和潜在应用。     

Ferrocene-containing carbohydrate dendrimers

Aliphatic amines, incorporating one or three (branched) acylated beta-D-glucopyranosyl residues, were coupled with the acid chloride of ferrocenecarboxylic acid and with the diacid chloride of 1,1'-ferrocenedicarboxylic acid to afford four dendrimer-type, carbohydrate-coated ferrocene derivatives in good yields (54-92%). Deprotection of the peracylated beta-D-glucopyranosyl residues was achieved quantitatively by using Zemplén conditions, affording four water-soluble ferrocene derivatives. When only one of the two cyclopentadienyl rings of the ferrocene unit is substituted, strong complexes are formed with beta-cyclodextrin in H2O, as demonstrated by liquid secondary ion mass spectrometry (LSIMS), 1H NMR spectroscopy, electrochemical measurements, and circular dichroism spectroscopy. Molecular dynamics calculations showed that the unsubstituted cyclopentadienyl ring is inserted through the cavity of the toroidal host in these complexes. The electrochemical behavior of the protected and deprotected ferrocene-containing dendrimers was investigated in acetonitrile and water, respectively. The diffusion coefficient decreases with increasing molecular weight of the compound. The potential for oxidation of the ferrocene core, the rate constant of heterogeneous electron transfer, and the rate constant for the energy-transfer reaction with the luminescent excited state of the [Ru(bpy)3]2+ complex (bpy = 2,2'-bipyridine) are strongly affected by the number (one or two) of substituents and by the number (one or three) of carbohydrate branches present in the substituents. These effects are assigned to shielding of the ferrocene core by the dendritic branches. Electrochemical evidence for the existence of different conformers for one of the dendrimers in aqueous solution was obtained.     

Water-soluble stilbene dendrimers

The third generation of novel photo-responsive water-soluble stilbene dendrimer (trans- and cis-G3 WSD) undergoes unusual one-way trans-to-cis isomerization to give 100% of cis isomer at the photostationary state on UV irradiation in water.     

Catalytic chameleon dendrimers

Dendrimers with boronic ester end-groups and an iron porphyrin core were synthesized and characterized. The dendrimer termini were reversibly exchanged by the addition of appropriate diol molecules. According to molecular dynamics (MD) simulations, the exchange of termini may lead to changes in the conformational behavior of the dendrimer, specifically regarding the average position of the end groups relative to the core. The spatial steric disposition attained with different termini was shown to significantly affect epoxidation reaction activity and selectivity with various alkenes, thus allowing for an original way to control and adjust catalytic behavior under alternating environments.     

Ferrocene-containing liquid-crystalline dendrimers

We describe the synthesis and liquid-crystalline properties of two ferrocene-containing liquid-crystalline dendrimers of second generation, which differentiate by the position of the ferrocene unit within the structure and by the nature of the mesomorphic promoters. Both dendrimers gave rise to smectic phases in agreement with their structures. The title compounds were prepared by applying a convergent synthesis. To cite this article: T. Chuard et al., C. R. Chimie 6 (2003).     

Water-soluble azobenzene dendrimers

Water-soluble azobenzene-cored dendrimers 4-6 were synthesized as potential photoresponsive micelles to which the aggregation is triggered by photoirradiation. In the absorption spectra, the π- absorption band of the dendrimers largely blue-shifted with increasing the generation due to the shielding effect of surrounding dendron on the interaction between the core azobenzene and solvent water. Not only the surrounding dendron groups suppressed the E-to-Z photoisomerization, but also the rate of thermal Z-to-E isomerization depended on the generation of the dendrimer. Furthermore, we have observed a novel temperature dependence of the rate constant of the thermal isomerization.