Neocarzilin A Is a Potent Inhibitor of Cancer Cell Motility Targeting VAT-1 Controlled Pathways.

The natural product neocarzilin A () was discovered decades ago, and despite its potent cytotoxic effects no mode of action studies have been performed up to date. Synthesis of neocarzilins A, B, and C and a stereoisomer of provided insights into structural preferences as well as access to probes for functional studies.  turned out to be the most active member and was not only effective against cell proliferation but also migration, a novel and so far overlooked activity.

Profiling withanolide A for therapeutic targets in neurodegenerative diseases.

To identify new potential therapeutic targets for neurodegenerative diseases, we initiated activity-based protein profiling studies with withanolide A (WitA), a known neuritogenic constituent of Withania somnifera root with unknown mechanism of action. Molecular probes were designed and synthesized, and led to the discovery of the glucocorticoid receptor (GR) as potential target. Molecular modeling calculations using the VirtualToxLab predicted a weak binding affinity of WitA for GR.

Bifunctional Duocarmycin Analogues as Inhibitors of Protein Tyrosine Kinases.

Bifunctional duocarmycin analogues are highly cytotoxic compounds that have been shown to be irreversible aldehyde dehydrogenase 1 inhibitors. Interestingly, cells with low aldehyde dehydrogenase 1 expression are also sensitive to bifunctional duocarmycin analogues, suggesting the existence of another target. Through in silico approaches, including principal component analysis, structure-similarity search, and docking calculations, protein tyrosine kinases, and especially the vascular endothelial growth factor receptor 2 (VEGFR-2), were predicted as targets of bifunctional duocarmycin analogues.

Influence of wing-tip substituents and reaction conditions on the structure, properties and cytotoxicity of Ag(i)- and Au(i)-bis(NHC) complexes.

The formation of different conformers of dinuclear silver(i) and gold(i) 1,1'-(2-hydroxyethane-1,1-diyl) bridge-functionalized bis(NHC) complexes with various wing-tip substituents (R = methyl, isopropyl and mesityl) has been investigated using multinuclear NMR spectroscopy and SC-XRD as well as DFT calculations. The ratio of anti/syn isomers strongly depends both on wing-tip substituents and the metal. Moreover, the reaction temperature plays a significant role during the transmetallation process for the ratio of gold(i) conformers, which is further affected by purification procedures.

A Whole Proteome Inventory of Background Photocrosslinker Binding.

Affinity-based protein profiling (AfBPP) is a widely applied method for the target identification of bioactive molecules. Probes containing photocrosslinkers, such as benzophenones, diazirines, and aryl azides, irreversibly link the molecule of interest to its target protein upon irradiation with UV light. Despite their prevalent application, little is known about photocrosslinker-specific off-targets, affecting the reliability of results.

Alkynol natural products target ALDH2 in cancer cells by irreversible binding to the active site.

Falcarinol and stipudiol are natural products with potent anti-cancer activity found in several vegetables. Here, we use a chemical proteomic strategy to identify ALDH2 as a molecular target of falcarinol in cancer cells and confirm enzyme inhibition via covalent alkylation of the active site. Furthermore, the synthesis of stipudiol led to the observation that ALDH2 exhibits preference for alkynol-based binders.

Chemical proteomics: ligation and cleavage of protein modifications.

Bioorthogonal ligation and cleavage methods are of major importance in the field of chemical biology. Recently, there has been significant progress in the improvement of classic ligation procedures as well as in the establishment of new ligation methodologies. Furthermore, the design of cleavable linkers for protein enrichment has lately received much attention.