No abstract

Adenine flips out: A combination of X‐ray crystallography, 2‐aminopurine fluorescence labeling, and the use of aminoglycosides as ligands is exploited to demonstrate conformational transitions in the RNA domain that ensures accurate protein synthesis (see picture). The triggering of a conformational change of an adenine unit in the RNA by ligand binding can be used as the basis of a screening method to discover antibiotics.

No abstract

The bisorbicillinoids are a growing class of novel natural products endowed with unique biological activity and are associated with fascinating hypotheses for their biosynthesis. A full account of our biomimetic explorations toward the bisorbicillinoids including the total syntheses of bisorbicillinol (1), bisorbibutenolide (2), and trichodimerol (4) from sorbicillin (3) is disclosed. Utilizing the novel dimerization reactions discovered and fine-tuned en route to 1 and 4, several analogues of these natural products have been synthesized. Furthermore, studies on the scope of these novel cycloaddition reactions and the isolation of a number of unexpected products along with proposed mechanisms for their formation are reported. These findings add to our knowledge of the largely unexplored chemistry of o-quinols and related aromatic systems.

A general reaction protocol for catalytic enantioselective 1,3-dipolar cycloaddition reaction of nitrones, activated by chiral Lewis acids, with electron-rich alkenes has been developed. The nitrones are activated by various chiral 2,2‘-dihydroxy-1,1‘-binaphthyl (BINOL)-AlMe complexes, and it has been found that 3,3‘-diaryl-BINOL-AlMe complexes catalyze a highly regio-, diastereo-, and enantioselective 1,3-dipolar cycloaddition reaction of aromatic nitrones with vinyl ethers, giving the exo-diastereomer of the isoxazolidines with de's up to >90% and up to 97% ee. The reaction has been investigated under various conditions with different nitrones and vinyl ethers (and alkenes), and a general synthetic procedure is presented. The mechanism for the reaction is discussed on the basis of a linear stereochemical effect of the catalyst, the diastereoselectivity, and absolute stereochemistry of the isoxazolidines formed, and theoretical calculations of the 3,3‘-diphenyl-BINOL-AlMe−nitrone intermediate.

Adenin dreht sich raus: Röntgenkristallographie, Fluoreszenzmarkierung mit 2‐Aminopurin und die Verwendung von Aminoglycosiden als Liganden ermöglichten den Nachweis von Konformationsänderungen an der RNA‐Domäne, die die richtige Proteinsynthese sicherstellt (siehe Bild). Das Auslösen einer Änderung der Konformation einer RNA‐Adenineinheit durch die Bindung von Liganden kann als Grundlage für eine Methode zur Suche nach Antibiotika dienen.

No abstract

We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.