The ligation of active pharmaceutical ingredients (API) for working with image processing systems in diagnostics (MRT) attracts increasing notice and scientific interest. The Diels-Alder ligation Reaction with inverse electron demand (DAR inv ) turns out to be an appropriate candidate. The DAR inv is characterized by a specific distribution of electrons of the diene and the corresponding dienophile counterpart. Whereas the reactants in the classical Diels-Alder Reaction feature electron-rich diene and electron-poor dienophile compounds, the DAR inv exhibits exactly the opposite distribution of electrons. Substituents with pushing electrones increase and, with pulling electrons reduce the electron density of the dienes as used in the DAR inv . We report here that the DAR inv is an efficient route for coupling of multifunctional molecules like active peptides, re-formulated drugs or small molecules like the alkyalting agent temozolomide (TMZ). This is an example of our contribution to the "Click chemistry" technology. In this case TMZ is ligated by DAR inv as a cargo to transporter molecules facilitating the passage across the cell membranes into cells and subsequently into subcellular components like the cell nucleus by using address molecules. With such constructs we achieved high local concentrations at the desired target site of pharmacological action. The DAR inv ligation was carried out using the combination of several technologies, namely: the organic chemistry and the solid phase peptide synthesis which can produce 'tailored' solutions for questions not solely restricted to the medical diagnostics or therapy, but also result in functionalizations of various surfaces qualified amongst others also for array development. We like to acquaint you with the DAR inv and we like to exemplify that all ligation products were generated after a rapid and complete reaction in organic solutions at room temperature, in high purity, but also, hurdles and difficulties on the way to the TMZ-BioShuttle conjugate should be mentioned. With this report we would like to stimulate scientists working with the focus on "Click chemistry" to intensify research with this expanding DAR inv able to open the door for new solutions inconceivable so far.
Progress in genome research led to new perspectives in diagnostic applications and to new promising therapies. On account of their specificity and sensitivity, nucleic acids (DNA/RNA) increasingly are in the focus of the scientific interest. While nucleic acids were a target of therapeutic interventions up to now, they could serve as excellent tools in the future, being highly sequence-specific in molecular diagnostics. Examples for imaging modalities are the representation of metabolic processes (Molecular Imaging) and customized therapeutic approaches (“Targeted Therapy”). In the individualized medicine nucleic acids could play a key role; this requires new properties of the nucleic acids, such as stability. Due to evolutionary reasons natural nucleic acids are substrates for nucleases and therefore suitable only to a limited extent as a drug. To use DNA as an excellent drug, modifications are required leading e.g. to a peptide nucleic acid (PNA). Here we show that an easy substitution of nucleobases by functional molecules with different reactivity like the Reppe anhydride and pentenoic acid derivatives is feasible. These derivatives allow an independent multi-ligation of functionalized compounds, e.g. pharmacologically active ones together with imaging components, leading to local concentrations sufficient for therapy and diagnostics at the same time. The high chemical stability and ease of synthesis could enhance nucleic chemistry applications and qualify PNA as a favourite for delivery. This system is not restricted to medicament material, but appropriate for the development of new and highly efficient drugs for a sustainable pharmacy.
Background: Curcumin can overcome CsA resistance. However, the molecular mechanism is unknown. Results: Curcumin blocks T cell stimulation-induced Ca 2ϩ mobilization and thereby prevents NFAT activation, a mechanism different from CsA. Conclusion: Curcumin is an immunosuppressive phytochemical that blocks Ca 2ϩ signaling. Significance: The study demonstrates for the first time that curcumin is a potent inhibitor of NFAT activation via blocking Ca
With the aim of establishing a versatile and easy synthesis of branched saccharides for biological applications, we used molecular-dynamics simulations to model Lewis(y) to two classes of di- or triantennary saccharide mimetics. One set of mimetics was based on 1,3,5-tris(hydroxymethyl)cyclohexane (TMC) as the core, the other on furan, and both were derivatised with galactose and/or fucose. The TMC-based saccharides were biotinylated, while the furan disaccharides were treated with maleimide-activated biotin in a Diels-Alder fashion to yield oxazatricyclodecanes (OTDs). These were then assayed as cell-surface labels in human colon (SW480 and CaCo-2), liver (PLC), Glia (U333 CG 343) and ovary (SKOV-3) tumour cell lines. Discrete staining patterns were observed in all cells, usually at one or two poles of the cells, particularly with the asymmetric 3-beta-L-fucopyranosyloxymethyl-4-beta-D-galactopyranosyloxymethyl-OTD. Normal SV40-transformed fibroblasts (SV80) showed no staining. Adhesion of the highly metastatic mouse melanoma line B16 F10 to fibronectin was inhibited by 80 % by the TMC-digalactoside and by 30 % by 3,4-bis-(beta-D-galactopyranosyloxymethyl)furan. None of the saccharide mimetics inhibited the adhesion of the less metastatic B16 F1 line. Migration of B16 F10 cells through Matrigel was greatly inhibited by the TMC-digalactoside and weakly inhibited by the TMC-trigalactoside. The saccharide mimetics that had shown the best structural agreements with the terminal saccharides of Lewis(y) in the molecular dynamics simulation were also the most biologically potent compounds; this underlines the predictive nature of molecular dynamics simulations. The use of the non-saccharide cores enabled us to adapt spacer lengths and terminal saccharides to optimise the structures to bind more avidly to cell-surface lectins.
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