Stefan Hillebrand

Hydroxyureas as Noncovalent Proteasome Inhibitors

Inhibitors with a new mechanism of action are needed for 20S proteasome (CP) inhibition owing to the ineffectiveness of current market drugs against some types of solid tumors. A novel class of nonpeptidic CP inhibitors has been developed, which display reversible and noncovalent binding. The structure-based design of these highly active and site-specific inhibitors revealed unexplored binding subpockets.

Asymmetric Total Synthesis of the Immunosuppressant (! )-Pironetin**

Independently isolated by Yoshida et al. and Kobayashi and co-workers from Streptomyces sp. NK-10958 and the fermentation broths of Streptomyces prunicolor PA-48153, ( )-Pironetin (1) was found to display plant-growth-regulatory as well as immunosuppressive activities similar to those exhibited by cyclosporin A (CsA) and FK-506. More recently, ( )-pironetin has since been identified as a strong antitumor agent that influences the dynamics of the tubulin– microtubules system by inhibiting the polymerization of tubulin. Interestingly, whereas other antitumor agents such as colchicin, vinblastin, rhizoxin, and epothilone B, bind to btubulin, ( )-pironetin was shown to bind to the a subunit of tubulin.

On the Antibiotic and Antifungal Activity of Pestalone, Pestalachloride A, and Structurally Related Compounds

Pestalone (1) is a prominent marine natural product first isolated by M. Cueto et al. in 2001 from a co-fermentation of a marine fungus with a marine bacterium. For more than 10 years, 1 had been considered as a promising new antibiotic compound, the reported MIC against methicillin-resistant Staphylococcus aureus (MRSA) being 37 ng/mL. After overcoming the limited availability of 1 by total synthesis (N. Slavov et al., 2010) we performed new biological tests, which did not confirm the expected degree of antibiotic activity. The observed activity of pestalone against different MRSA strains was 3-10 μg/mL, as determined independently in two laboratories. A number of synthetic derivatives of 1 including pestalachloride A and other isoindolinones (formed from 1 by reaction with amines) did not exhibit higher activities as compared to 1 against MRSA and a series of plant pathogens.

Modular, Concise, and Efficient Synthesis of Highly Functionalized 5-Fluoropyridazines by a [2 + 1]/[3 + 2]-Cycloaddition Sequence

An easy access to 5-fluoropyridazines by a [2 + 1]/[3 + 2]-cycloaddition sequence between terminal alkynes, a difluorocarbene, and a diazo compound is reported. This approach does not necessitate the isolation of any intermediates, and a wide range of novel 5-fluoropyridazines was synthesized from readily available starting materials. Additionally, these compounds were used as a platform to access novel and highly diversified pyridazines.

Palladium-catalyzed phosphonylation: synthesis of C3-, C4-, and C5-phosphonylated pyrazoles.

A palladium-catalyzed cross-coupling between 3-, 4-, and 5-halo-pyrazoles and H-phosphonates, H-phosphinates, and secondary phosphine oxides has been developed. This coupling reaction constitutes the first general method allowing the introduction of a great diversity of phosphorus substituents on the different carbons of the pyrazole ring in a one-step process.