Antimicrobial Peptides Incorporating Halogenated Marine-Derived Amino Acid Substituents.

Small synthetic mimics of cationic antimicrobial peptides represent a promising class of compounds with leads in clinical development for the treatment of persistent microbial infections. The activity and selectivity of these compounds rely on a balance between hydrophobic and cationic components, and here, we explore the activity of 19 linear cationic tripeptides against five different pathogenic bacteria and fungi, including clinical isolates. The compounds incorporated modified hydrophobic amino acids inspired by motifs often found in bioactive marine secondary metabolites in combination with different cationic residues to probe the possibility of generating active compounds with improved safety profiles. Several of the compounds displayed high activity (low µM concentrations), comparable with the positive controls AMC-109, amoxicillin, and amphotericin B. A higher activity was observed against the fungal strains, and a low in vitro off-target toxicity was observed against erythrocytes and HeLa cells, thereby illustrating effective means for tuning the activity and selectivity of short antimicrobial peptides.

Structural Basis of Metallo-ß-lactamase Inhibition by N-Sulfamoylpyrrole-2-carboxylates.

Metallo-ß-lactamases (MBLs) can efficiently catalyze the hydrolysis of all classes of ß-lactam antibiotics except monobactams. While serine-ß-lactamase (SBL) inhibitors (e.g., clavulanic acid, avibactam) are established for clinical use, no such MBL inhibitors are available. We report on the synthesis and mechanism of inhibition of N-sulfamoylpyrrole-2-carboxylates (NSPCs) which are potent inhibitors of clinically relevant B1 subclass MBLs, including NDM-1. Crystallography reveals that the N-sulfamoyl NH2 group displaces the dizinc bridging hydroxide/water of the B1 MBLs. Comparison of crystal structures of an NSPC and taniborbactam (VRNX-5133), presently in Phase III clinical trials, shows similar binding modes for the NSPC and the cyclic boronate ring systems. The presence of an NSPC restores meropenem efficacy in clinically derived E. coli and K. pneumoniae blaNDM-1. The results support the potential of NSPCs and related compounds as efficient MBL inhibitors, though further optimization is required for their clinical development.

Site-Selective and Stereoselective C-H Functionalization of N-Cyclopropylamides via a Directed Remote Metalation Strategy.

A new methodology for site-selective and stereoselective C-H functionalization of aminocyclopropanes via directed remote lithiation has been developed. Treatment of N-directing group (DG = pivaloyl, tetramethylsuccinimidoyl) arylcyclopropanes with t-BuLi results in a clean ß-lithiation and, following quench with electrophiles, leads to a range of cyclopropane derivatives. Sequential double lithiation-methylation to give a dimethylated cyclopropane has been achieved. X-ray, NMR, and computational studies allow rationalization of syn-DG ß-deprotonation selectivity via a DG-lithium base coordinated complex.

Synthesis of ergostane-type brassinosteroids with modifications in ring A.

Herein, we present a new strategy for the preparation of a broad range of brassinosteroid biosynthetic precursors/metabolites differing by the ring A fragment. The protocol is based on the use of readily available phytohormones of this class bearing a 2α,3α-diol moiety (epibrassinolide or epicastasterone) as starting materials. The required functionalities (Δ2-, 2α,3α- and 2ß,3ß-epoxy-, 2α,3ß-, 2ß,3α-, and 2ß,3ß-dihydroxy-, 3-keto-, 3α- and 3ß-hydroxy-, 2α-hydroxy-3-keto-) were synthesized from 2α,3α-diols in a few simple steps (Corey-Winter reaction, epoxidation, oxidation, hydride reduction, etc.).

Brassinosteroid-BODIPY conjugates: Design, synthesis, and properties.

Three BS-BODIPY (brassinosteroids-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) conjugates were synthesized and their fluorescent and immunological properties were investigated. Two of the conjugates, having present all the functional groups characteristic of BS, were shown to be potentially useful as biological probes to study involvement of BS into physiological processes in living cells.

A new synthesis of brassinosteroids with a cholestane framework based on a highly functionalized starting material.

A new route to the synthesis of minor brassinosteroids with a cholestane framework (28-norcastasterone and 28-norbrassinolide) has been proposed. It makes use of commercially available 24-epicastasterone as a starting material. In addition, [26,26,26-(2)H3]-28-norcastasterone and [26,26,26-(2)H3]-28-norbrassinolide have been prepared as tools for analytical applications. The key steps were regioselective manipulations of functional groups in 24-epicastasterone, oxidative cleavage of 22,23-diol group and Claisen rearrangement.