Structure-based design, synthesis and A-site rRNA co-crystal complexes of novel amphiphilic aminoglycoside antibiotics with new binding modes: a synergistic hydrophobic effect against resistant bacteria.

Incorporation of an hydrophobic (phenethylamino)ethyl ether at C2″ of N1-(HABA)-3',4'-dideoxyparomomycin led to a novel analog with an excellent antibacterial profile against a host of resistant bacteria.

Crystal structure of the bacterial ribosomal decoding site complexed with a synthetic doubly functionalized paromomycin derivative: a new specific binding mode to an a-minor motif enhances in vitro antibacterial activity.

The crystal structure of the complex between oligonucleotide containing the bacterial ribosomal decoding site (A site) and the synthetic paromomycin analogue 1, which contains the gamma-amino-alpha-hydroxybutyryl (L-haba) group at position N1 of ring II (2-DOS ring), and an ether chain with an O-phenethylaminoethyl group at position C2'' of ring III, is reported. Interestingly, next to the paromomycin analogue 1 specifically bound to the A site, a second molecule of 1 with a different conformation is observed at the crystal packing interface which mimics the A-minor interaction between two bulged-out adenines from the A site and the codon-anticodon stem of the mRNA-tRNA complex. Improved antibacterial activity supports the conclusion that analogue 1 might affect protein synthesis on the ribosome in two different ways: 1) specific binding to the A site forces maintenance of the "on" state with two bulged out adenines, and 2) a new binding mode of 1 to an A-minor motif which stabilizes complex formation between the ribosome and the mRNA-tRNA complex regardless of whether the codon-anticodon stem is of the cognate or near-cognate type.

Reversed approach to S-farnesylation and S-palmitoylation: application to an efficient synthesis of the C-terminus of lipidated human N-ras hexapeptide.

[reaction: see text] A general reversed approach is described to synthesize S-palmitoylated and S-farnesylated peptides via S(N)2 displacement of bromide by reaction of a thiol group containing lipid as nucleophile with bromoalanine-containing peptides as electrophile. By employing this approach, lipidated peptides, including characteristic partial structures of human Ras peptides, were synthesized in good yields. This method gives access to farnesylated, palmitoylated, and doubly lipidated peptides.

Straightforward synthesis of gem-phosphonate-phosphate containing compounds via one-pot reaction of thioesters with diethyl phosphite.

A convenient straightforward, three step, one-pot reaction of diethyl phosphite with thioesters in the presence of catalytic amounts of potassium tert-butoxide in toluene or DMF as solvent provided various phosphonate-phosphate containing compounds in excellent yields.

Synthesis of novel S-neoglycopeptides from glycosylthiomethyl derivatives.

Reaction of glycosylthiomethyl azides with amino acid and peptide derivatives containing aspartate and glutamate thio acids gave the corresponding glycosylthiomethyl amides in excellent yields. Another type of neoglycopeptides was obtained via reaction of glycosylthiomethyl bromide with cysteine and homocysteine containing peptide derivatives, thus affording the corresponding S-(glycosylthiomethyl) peptides.

Synthesis of S-linked glycopeptides in aqueous solution.

Investigation of direct S-glycosylation of homocysteine and cysteine containing peptides with O-acetyl protected glycosyl halides led under two-phase conditions in the presence of sodium carbonate as base to excellent results. Thus, from glucosyl bromide, galactosyl bromide, lactosyl bromide, sialyl chloride, and N-Troc protected 2-amino-2-deoxyglucosyl bromide S-glycosylated dipeptides 15, 18-21, 23, 24, and 26-29, respectively, were obtained in excellent yields. Alternatively, depending on the solubility of the peptide moiety, mixtures of DMF and water could be employed for successfully carrying out this reaction. Thus, S-glycosylated tripeptides 42-45 could be obtained. Combination of this method with chemical ligation was also successfully carried out.