Karl Baumann

Discovery of topical calcineurin inhibitors and pharmacological profile of pimecrolimus

Using a newly developed model of allergic contact dermatitis in pigs, calcineurin inhibitors of the tacrolimus and ascomycin type were shown to have a highly anti-inflammatory action after topical application. These findings provided the first pharmacological evidence of the efficacy of this novel class of topical agents in the treatment of inflammatory skin diseases, and, thus, their potential to become the first alternative to corticosteroids in more than 40 years. As a result of a large research program into ascomycins, pimecrolimus (Elidel®, SDZ ASM 981) was selected for development due to its favorable pharmacology and safety profile, alongside tacrolimus (Protopic®, FK 506). In vitro, pimecrolimus inhibits the transcription and release of pro-inflammatory cytokines in T cells. Similar to the corticosteroids, betamethasone-17-valerate and dexamethasone, pimecrolimus is effective at nanomolar concentrations. Targeting mainly T cells, pimecrolimus has, however, a more specific mode of action. Moreover, in contrast to corticosteroids, pimecrolimus has no effect on Langerhans’ cells, the professional antigen- presenting dendritic cells of the skin that are crucial for local immunosurveillance. When applied topically, pimecrolimus exerts a high and selective anti-inflammatory activity in the skin, shows minimal percutaneous absorption, and has a low potential to affect systemic immunoreactions. Pimecrolimus cream 1% has proven to be well tolerated, safe, and highly effective in clinical studies in patients with atopic dermatitis.

Synthesis and oxidative cleavage of the major equilibrium products of ascomycin and FK 506

Abstract Ascomycin and FK 506 are converted into the 9-ketal isomers in high yields by simple treatment with Lewis acids. The structure of the 9-ketal isomer was confirmed by oxidative cleavage.

Highly selective reactions of FK506 with diazomethane

Abstract Three modes of diazomethane reactivity, namely oxirane formation, O-methylation and cyclopropanation, can be accomplished with excellent selectivity on the multifunctional molecule FK506.

Highly selective TFAA-cleavage of tertiary 2,4-dimethoxybenzylamines and its use in the synthesis of secondary amines

Abstract TFAA-treatment of allylic, propargylic, homopropargylic and some benzylic tert. 2,4-dimethoxybenzylamines leads to highly selective cleavage of their dimethoxybenzylic CN bonds. The resultant trifluoroacetamides can then readily be converted to the corresponding secondary amines.

Synthesis and Acetylcholinesterase Inhibition of 5-Desamino Huperzine A Derivatives

(E)- and (Z)-5-Desamino huperzine A derivatives have been synthesized using a new synthetic strategy towards the huperzine A skeleton. These derivatives showed AChE inhibition constants in the low micromolar range and thus display better activity than all previously synthesized C5 derivatives.

SYNTHETIC MODIFICATIONS OF ASCOMYCIN. I: A CHEMOSELECTIVE REMOVAL OF THE CYCLOHEXYL RESIDUE OF ASCOMYCIN

Abstract An efficient semisynthetic preparation of des-28-(cyclohexyl)methylene-28-oxo-ascomycin derivatives starting from 24,33- O -bis( tert -butyldimethylsilyl)-ascomycin ( 1 ) is described. The strategy for preparing 28-oxo-ascomycin derivatives involves the reduction of C-22 carbonyl group, followed by 5-endo-cyclization of the resulting C-22 alcohol with the C-19/C-20 double bond using an oxymercuration reaction; ozonolysis of the C-28/C-29 double bond and regeneration of the C-19/C-20 double bond. Further, the 20-mercury-substituted ascomycin derivatives could be reduced to the corresponding metal free cyclic ethers using n -Bu 3 SnH.

Synthesis of (±)-desamino huperzine A

Abstract The first synthesis of desamino huperzine A 2 is described. Key steps are a double Michael addition into benzoquinone monoketal 4 , a regiocontrolled double bond isomerisation and a novel pyridone synthesis involving a Michael addition of a β-keto ester into acrylonitrile.

CARBONYL TO METHYLENE CONVERSIONS AT THE TRICARBONYL-PORTION OF ASCOMYCIN DERIVATIVES

Abstract Treatment of ascomycin or its O-TBDMS-derivatives with hydrogen sulfide and pyridine in dimethylformamide solution results in deoxygenation reactions at the tricarbonyl sequence of the binding domain. 9-deoxo-ascomycins ( 5a-c ) are obtained in high yields (75–85%) together with small amounts (2–14% yield) of 10-deoxo-ascomycins ( 6a-c ). The novel derivative 10-deoxo-ascomycin ( 6a ) is accessible in excellent yield (85%) from the 10-amino-analog of ascomycin upon reaction with hydrogen sulfide in the absence of base.

Tetrahydroanthraquinone Derivative (±)-4-Deoxyaustrocortilutein Induces Cell Cycle Arrest and Apoptosis in Melanoma Cells via Upregulation of p21 and p53 and Downregulation of NF-kappaB

Background: Malignant melanoma is an aggressive type of skin cancer with high risk for metastasis and chemoresistance. Disruption of tightly regulated processes such as cell cycle, cell adhesion, cell differentiation and cell death are predominant in melanoma development. So far, conventional treatment options have been insufficient to treat metastatic melanoma and survival rates are poor. Anthraquinone compounds have been reported to have anti-tumorigenic potential by DNA-interaction, promotion of apoptosis and suppression of proliferation in various cancer cells. Methods: In the current study, the racemic tetrahydroanthraquinone derivative (±)-4-deoxyaustrocortilutein (4-DACL) was synthesized and the cytotoxic activity against melanoma cells and melanoma spheroids determined by CellTiter-Blue viability Assay and phase contrast microscopy. Generation of reactive oxygen species (ROS) was determined with CellROX Green and Deep Red Reagent kit and microplate-based fluorometry. Luciferase reporter gene assays for nuclear factor kappa B (NF-κB) and p53 activities and western blotting analysis were carried out to detect the expression of anti-proliferative or pro-apoptotic (p53, p21, p27, MDM2, and GADD45M) and anti-apoptotic (p65, IκB-α, IKK) proteins. Cell cycle distribution and apoptosis rate were detected by flow cytometry, the morphological changes visualized by fluorescence microscopy and the activation of different caspase cascades distinguished by Caspase Glo 3/7, 8 and 9 Assays. Results: We demonstrated that 4-DACL displayed high activity against different malignant melanoma cells and melanoma spheroids and only low toxicity to melanocytes and other primary cells. In particular, 4-DACL treatment induced mitochondrial ROS, reduced NF-κB signaling activity and increased up-regulation of the cell cycle inhibitors cyclin-dependent kinase inhibitor p21 (p21WAF1/Cip1) and the tumor suppressor protein p53 in a dose-dependent manner, which was accompanied by decreased cell proliferation and apoptosis via the intrinsic pathway. Conclusion: According to these results, we suggest that 4-DACL may be a promising therapeutic agent for the treatment of malignant melanoma.

Complete assignment of 1H and 13C NMR data of pravastatin derivatives

The complete 1H and 13C NMR data of 27 pravastatin derivatives are presented. Assignment was achieved by use of 1D and 2D NMR experiments (selective 1D NOE, COSY, NOESY, HSQC, HMBC). Copyright