Short antimicrobial peptides rich in arginine (R) and tryptophan (W) interact with membranes. To learn how this interaction leads to bacterial death, we characterized the effects of the minimal pharmacophore RWRWRW-NH 2 . A ruthenium-substituted derivative of this peptide localized to the membrane in vivo, and the peptide also integrated readily into mixed phospholipid bilayers that resemble Gram-positive membranes. Proteome and Western blot analyses showed that integration of the peptide caused delocalization of peripheral membrane proteins essential for respiration and cell-wall biosynthesis, limiting cellular energy and undermining cell-wall integrity. This delocalization phenomenon also was observed with the cyclic peptide gramicidin S, indicating the generality of the mechanism. Exogenous glutamate increases tolerance to the peptide, indicating that osmotic destabilization also contributes to antibacterial efficacy. Bacillus subtilis responds to peptide stress by releasing osmoprotective amino acids, in part via mechanosensitive channels. This response is triggered by membrane-targeting bacteriolytic peptides of different structural classes as well as by hypoosmotic conditions. mechanism of action | respiratory chain | hypoosmotic stress response | metallocenes

Lysine and arginine methyltransferases participate in the post-translational modification of histones and regulate key cellular functions. So far only one arginine methyltransferase inhibitor discovered by random screening was available. We present the first target-based approach to protein arginine methyltransferase (PRMT) inhibitors. Homology models of human and Aspergillus nidulans PRMT1 were generated from available X-ray structures of rat PRMTs. The NCI diversity set was filtered by a target-based virtual screening to identify PRMT inhibitors. Employing a fungal PRMT for screening and a human enzyme for validation, we have identified seven inhibitors of PRMTs in vitro. Hit validation was achieved for two new inhibitors by antibody mediated detection of histone hypomethylation as well as Western blotting in cancer cells. Functional activity was proven by an observed block of estrogen receptor activation. Thus, valuable chemical tools and potential drug candidates could be identified.

Aspirin, the acetyl ester of salicylic acid, was first discovered in the late 1800s and became one of the most world-renowned drugs. Its fame is rooted in its ability to treat a wide range of symptoms such as fever, inflammation, and pain. Aspirin represents an advancement of the previously applied salicylic acid, which was obtained from myrtle leaf decoction or willow bark extract, but was found to be less active and to cause serious gastrointestinal irritation.[1] Later on, other chemical modifications of aspirin were investigated with the aim of improving its pharmacological profile. The influence of additional substituents on the phenyl ring and modification of the acetoxy and carboxy groups were studied, [2] and even the phenyl core of aspirin was replaced by the organometallic ferrocene moiety. [3] However, none of these derivatives could substitute for aspirin. We have now modified aspirin by replacing the phenyl ring with a three-dimensional and highly hydrophobic carbaborane cluster.Carbaboranes are already known in medicinal chemistry as phenyl group mimetics, and analogues of tamoxifen, [4] trimethoprim, [5] and transthyretin amyloidosis inhibitors derived from flufenamic acid and diflunisal, [6] two nonsteroidal anti-inflammatory drugs (NSAIDs), have been presented.The focal point of our research was a high-yield synthesis of asborin, the carbaborane analogue of aspirin, and the study of its pharmacological behavior. Asborin is obtained in three steps (Scheme 1) starting from ortho-dicarba-closo-dodecaborane(12) (1). In the first step one of the carbaborane carbon atoms is hydroxylated according to a protocol described by Endo and co-workers.[7] The monolithiated carbaborane is treated with trimethyl borate to give a carbaboranyl boronic ester in situ. The ester is then oxidized with peracetic acid. The second step is carboxylation of the second cluster carbon atom. Both the OH proton and the remaining carbaborane CH proton of 2 can be removed with n-butyllithium, and reaction of the resulting dilithium salt with gaseous carbon dioxide gives 1-hydroxy-1,2-dicarba-closo-dodecaborane(12)-2-carboxylic acid (3) in greater than 99 % yield after acidic workup. Compound 3, with an ortho arrangement of hydroxy and carboxy groups, is the carbaborane analogue of salicylic acid. Finally, 1-acetoxy-1,2-dicarba-closo-dodecaborane(12)-2-carboxylic acid (asborin, 4) is obtained quantitatively simply by stirring 3 in acetyl chloride. The use of acetyl chloride rather than acetic anhydride is advantageous, as it can easily be removed under reduced pressure due to its lower boiling point of 52 8C. Crystals of 4 suitable for X-ray crystallography ( Figure 1) were obtained from chloroform; hydrogen-bonded dimers are formed via the carboxy groups.Asborin, with its hydrophobic cluster framework and hydrophilic carboxy group, is remarkably amphiphilic: It dissolves in water and nonpolar organic solvents.Aspirin is one of the smallest members of the NSAID family. These compounds are structurally very diverse, but all of the...

This study hypothesized that long carbon chain cationic arginine (Arg) esters can be considered as toxicologically harmless preservatives. Arg-esters with C 18 and C 24 carbon chains, namely, arginine-oleate (Arg-OL) and arginine-decyltetradecanoate (Arg-DT), were synthesized. Structures were confirmed by FT-IR, 1 H NMR, and mass spectroscopy. Both Arg-esters were tested regarding hydrophobicity in terms of log P octanol/water , critical micelle concentration (CMC), biodegradability, cytotoxicity, hemolysis, and antimicrobial activity against Escherichia coli ( E . coli ), Staphylococcus aureus ( S . aureus ), Bacillus subtilis ( B . subtilis ), and Enterococcus faecalis ( E . faecalis ). Log P octanol/water of arginine was raised from −1.9 to 0.3 and 0.6 due to the attachment of C 18 and C 24 carbon chains, respectively. The critical micelle concentration of Arg-OL and Arg-DT was 0.52 and 0.013 mM, respectively. Both Arg-esters were biodegradable by porcine pancreatic lipase. In comparison to the well-established antimicrobials, benzalkonium chloride (BAC) and cetrimide, Arg-esters showed significantly less cytotoxic and hemolytic activity. Both esters exhibited pronounced antimicrobial properties against Gram-positive and Gram-negative bacteria comparable to that of BAC and cetrimide. The minimum inhibitory concentration (MIC) of Arg-esters was <50 μg mL –1 against all tested microbes. Overall, results showed a high potential of Arg-esters with long carbon chains as toxicologically harmless novel preservatives.

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