Bruno Bernet

Intramolecular OH⋅⋅⋅FC Hydrogen Bonding in Fluorinated Carbohydrates: CHF is a Better Hydrogen Bond Acceptor than CF2

An intramolecular bifurcated H-bond from the axial HO-2 group to the axial F-4 atom and to the O5 atom of α-D-hexopyranosides in apolar solvents is evidenced in (1)H NMR spectra. The H-accepting properties of the F atom are modulated by the orientation of the O-substituent at the C3 atom and by an additional F atom at the C4 atom.

Expanding the chemical structure space of opto-electronic molecular materials: unprecedented push-pull chromophores by reaction of a donor-substituted tetracyanofulvene with electron-rich alkynes.

The reaction of a 3,5-bis(N,N-dimethylanilino)-substituted 2,4,6,6-tetracyanopentafulvene (TCPF) with mono- and bis(N,N-dimethylanilino)acetylene provides facile access to push-pull chromophores with diverse new scaffolds. The starting TCPF reacts with bis(N,N-dimethylanilino)acetylene in a formal [2+2] cycloaddition at the exocyclic double bond, followed by retroelectrocyclization, to yield an ethenylene-extended push-pull pentafulvene. The transformation with 4-ethynyl-N,N-dimethylaniline also yields a similar extended pentafulvene as well as two other products that required X-ray analysis for their structure elucidation. One features an 8,8-dicyanoheptafulvene core formed by formal [2+2] cycloaddition, followed by ring opening via fragmentation. The second is a chiral cyclobutenylated tetrahydropentalene, resulting from a cascade of formal [6+2] and [2+2] cycloadditions. All new nonplanar push-pull chromophores display amphoteric redox behavior with both strong electron-donating and -accepting potency. Notably, the N,N-dimethylanilino-substituted extended pentafulvenes show remarkably low oxidation potentials (0.27/0.28 V vs Fc/Fc(+) reference) that are lower than those for N,N-dimethylaniline itself. The push-pull-substituted extended pentafulvenes feature intense electronic absorption bands, extending over the entire visible spectral range into the near infrared, and low highest occupied molecular orbital-lowest unoccupied molecular orbital gaps. These properties, together with high thermal stability and good solubility, suggest the potential use of the new chromophores as advanced materials in molecular electronics devices.

Structure-Activity Relationships among the Kanamycin Aminoglycosides: Role of Ring I Hydroxyl and Amino Groups

ABSTRACT The kanamycins form an important subgroup of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside antibiotics, comprising kanamycin A, kanamycin B, tobramycin, and dibekacin. These compounds interfere with protein synthesis by targeting the ribosomal decoding A site, and they differ in the numbers and locations of amino and hydroxy groups of the glucopyranosyl moiety (ring I). We synthesized kanamycin analogues characterized by subtle variations of the 2′ and 6′ substituents of ring I. The functional activities of the kanamycins and the synthesized analogues were investigated (i) in cell-free translation assays on wild-type and mutant bacterial ribosomes to study drug-target interaction, (ii) in MIC assays to assess antibacterial activity, and (iii) in rabbit reticulocyte translation assays to determine activity on eukaryotic ribosomes. Position 2′ forms an intramolecular H bond with O5 of ring II, helping the relative orientations of the two rings with respect to each other. This bond becomes critical for drug activity when a 6′-OH substituent is present.

Identification and evaluation of improved 4'-O-(alkyl) 4,5-disubstituted 2-deoxystreptamines as next-generation aminoglycoside antibiotics.

ABSTRACT The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4′ alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides—irreversible hearing loss. Compounds were evaluated for target activity in in vitro ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and in vivo ototoxicity. The results of this study produced potent compounds with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity. IMPORTANCE The ever-widening epidemic of multidrug-resistant infectious diseases and the paucity of novel antibacterial agents emerging from modern screening platforms mandate the reinvestigation of established drugs with an emphasis on improved biocompatibility and overcoming resistance mechanisms. Here, we describe the preparation and evaluation of derivatives of the established aminoglycoside antibiotic paromomycin that effectively remove its biggest deficiency, ototoxicity, and overcome certain bacterial resistance mechanisms. The ever-widening epidemic of multidrug-resistant infectious diseases and the paucity of novel antibacterial agents emerging from modern screening platforms mandate the reinvestigation of established drugs with an emphasis on improved biocompatibility and overcoming resistance mechanisms. Here, we describe the preparation and evaluation of derivatives of the established aminoglycoside antibiotic paromomycin that effectively remove its biggest deficiency, ototoxicity, and overcome certain bacterial resistance mechanisms.

Design and Synthesis of Aviram–Ratner-Type Dyads and Rectification Studies in Langmuir–Blodgett (LB) Films

The design and synthesis of Aviram-Ratner-type molecular rectifiers, featuring an anilino-substituted extended tetracyanoquinodimethane (exTCNQ) acceptor, covalently linked by the σ-spacer bicyclo[2.2.2]octane (BCO) to a tetrathiafulvalene (TTF) donor moiety, are described. The rigid BCO spacer keeps the TTF donor and exTCNQ acceptor moieties apart, as demonstrated by X-ray analysis. The photophysical properties of the TTF-BCO-exTCNQ dyads were investigated by UV/Vis and EPR spectroscopy, electrochemical studies, and theoretical calculations. Langmuir-Blodgett films were prepared and used in the fabrication and electrical studies of junction devices. One dyad showed the asymmetric current-voltage (I-V) curve characteristic for rectification, unlike control compounds containing the TTF unit but not the exTCNQ moiety or comprising the exTCNQ acceptor moiety but lacking the donor TTF part, which both gave symmetric I-V curves. The direction of the observed rectification indicated that the preferred electron current flows from the exTCNQ acceptor to the TTF donor.

Replacement of Water Molecules in a Phosphate Binding Site by Furanoside‐Appended lin‐Benzoguanine Ligands of tRNA‐Guanine Transglycosylase (TGT)

The enzyme tRNA-guanine transglycosylase has been identified as a drug target for the foodborne illness shigellosis. A key challenge in structure-based design for this enzyme is the filling of the polar ribose-34 pocket. Herein, we describe a novel series of ligands consisting of furanoside-appended lin-benzoguanines. They were designed to replace a conserved water cluster and differ by the functional groups at C(2) and C(3) of the furanosyl moiety being either OH or OMe. The unfavorable desolvation of Asp102 and Asp280, which are located close to the ribose-34 pocket, had a significant impact on binding affinity. While the enzyme has tRNA as its natural substrate, X-ray co-crystal structures revealed that the furanosyl moieties of the ligands are not accommodated in the tRNA ribose-34 site, but at the location of the adjacent phosphate group. A remarkable similarity of the position of the oxygen atoms in these two structures suggests furanosides as a potential phosphate isoster.

Swapping Interface Contacts in the Homodimeric tRNA‐Guanine Transglycosylase: An Option for Functional Regulation

The enzyme tRNA-guanine transglycosylase, a target to fight Shigellosis, recognizes tRNA only as a homodimer and performs full nucleobase exchange at the wobble position. Active-site inhibitors block the enzyme function by competitively replacing tRNA. In solution, the wild-type homodimer dissociates only marginally, whereas mutated variants show substantial monomerization in solution. Surprisingly, one inhibitor transforms the protein into a twisted state, whereby one monomer unit rotates by approximately 130°. In this altered geometry, the enzyme is no longer capable of binding and processing tRNA. Three sugar-type inhibitors have been designed and synthesized, which bind to the protein in either the functionally competent or twisted inactive state. They crystallize with the enzyme side-by-side under identical conditions from the same crystallization well. Possibly, the twisted inactive form corresponds to a resting state of the enzyme, important for its functional regulation.