Dr. Matthias Schmidt
Dr. rer. nat. Matthias Schmidt
Tel. 0345 55 25169 / 188
e-mail: matthias.schmidt(at)pharmazie.uni-halle.de
Development of new efflux pump inhibitors to overcome multidrug resistance
Multidrug resistance (MDR) to antitumor agents represents a major obstacle to a successful chemotherapy of cancer. Overexpression of P-glycoproteine (p-gp) seems to be the major factor responsible for MDR. A large number of chemically unrelated compounds are known to interact with p-gp resulting in a decreasing resistance. In our efforts related to structure-activity studies of new potential MDR reversal agents we are specialized in synthesis in new types of phenothiazines and other compounds that differ in the aromatic core structure, the linker and the basic moiety. For our search of new aromatic core structures we synthesize novel 2,2-diphenyl-1,3-dioxolane, 2,2-diphenyl-1,3-dioxane and 4,5-diphenyl-1,3-dioxolane derivatives. A range of lipophilic linker structures and protonable basic moieties were synthesized and investigated to optimize the structure of the potential MDR-modulators. The compounds are tested in vitro using LLC-PK1-MDR and human Caco-2 cells. Both the cytotoxicity of the synthons and their ability to resensitize the cells against chemotherapeutics like vinblastine or vinristine are determined with kristallvolett assay and MTT assay. The results show that at low concentration various substances reverse tumor cell MDR. Some of the new structures show better effects than established modulators like trifluoperazine.
Neo synthesis of glycolipid inhibitors of Myt1 kinase and structure-activity relationships of novell kinase inhibitors as suggestive extension to conventional chemotherapy and to overcome reistance
The enzyme Myt1 kinase is an impotant regulator of cdc2/cyclin B kinase activity. The inhibitory phosphorylation of cdc2 is important for the timing of entry into mitosis. Various studies have shown that premature activation of cdc2 leads to mitotic catastrophe and cell death. Inhibition of Myt1 kinase is predicted to cause premature activation of cdc2. So inhibitors of Myt1 kinase can kill rapidly proliferating cells and interfere cell cycle checkpoints. Such inhibitors could be a suggestive extension to conventional chemotherapy and to overcome resistance.
As result of a systematic search for potential anti-cancer agents from plants and marine organisms two bioactive glycoglycerolipids were isolated from a marine alga extract. The compounds show in a bioassay a higher activity against the enzyme Myt1 kinase than staurosporin as positive control.
Aim of our research is the neo-synthesis of these natural products, the systematical variation
of molecule domains and structure-activity relationships.
Development and comparison of bioassays for activity determination of potential Myt1 kinase inhibitors
The enzyme Myt1 kinase is a Thr-14 and Tyr-15 specific regulator of cdc2 kinase activity. The inhibitory phosphorylation of cdc2 is important for the timing of entry into mitosis. Various studies have shown that premature activation of cdc2 leads to mitotic catastrophe and cell death. Inhibition of Myt1 kinase is predicted to cause premature activation of cdc2. Therefore inhibitors of Myt1 kinase can kill rapidly proliferating cells and interfere cell cycle checkpoints. Such inhibitors could be a suggestive extension to conventional chemotherapy and to overcome resistance.
As result of a systematic search for potential anti-cancer agents from plants and marine organisms two bioactive glycoglycerolipids were isolated from a marine alga extract. The compounds show in a bioassay a higher activity against the enzyme Myt1 kinase than staurosporin as positive control.
Aim of our research is development and comparison of bioassays testing compounds synthesized in our team. The methods fluorescence polarization, gelelectrophoresis (western blot) und MS/MS-analysis are intended to be used. Thereby the extent of phosphorylation on Thr-14 and Tyr-15 can be determined with specific anti-phosho-Cdc2 antibody and so the inhibitor quality of our synthesized compounds can be evaluated.
Synthesis of glycosides with lipidanchor for investigation of biological recognition processes
A number of important recognition processes in biological systems are based on specific interactions of terminal carbohydrate residues of glycoconjugates with proteins. The study of the interaction of natural glycoconjugates (e.g. sialyl LewisX) with their receptors (e.g. E-selectin) demonstrate that different terminal carbohydrates with different distances between the hydrophobic and the recognition domain are responsible for an efficient ligand-receptor-binding.
We investigate new derivatives suitable for the synthesis of polyantennary cluster glycolipids. In order to synthesize mimetics of sialyl LewisX determinants we have chosen O-alkylated pentaerythritol as core substance. The selective protection of the three hydroxyl groups enables us to introduce various headgroups using different carbohydrates with or without ethoxy spacer of different lengths to simulate a variety in binding epitopes. Neoglycoconjugates with a certain degree of equal carbohydrates (mono-, bis- and trisglycosides) were synthesized and fully characterized by 1H-NMR and ESI-MS. Biochemical investigations demonstrate an increase of the binding affinity (concanavalin A) in case of glycoconjugates with two or three terminal headgroups (cluster effekt). A number of alternative reactions for the synthesise of cluster glycolipids via photoaddition of thiol derivatives with 1-O-allylglycosides were developed.