ABSTRACT
Clinical use of 2-deoxystreptamine aminoglycoside antibiotics, which target the bacterial ribosome, is compromised by adverse effects related to limited drug selectivity. Here we present a series of 4',6'-O-acetal and 4'-O-ether modifications on glucopyranosyl ring I of aminoglycosides. Chemical modifications were guided by measuring interactions between the compounds synthesized and ribosomes harbouring single point mutations in the drug-binding site, resulting in aminoglycosides that interact poorly with the drug-binding pocket of eukaryotic mitochondrial or cytosolic ribosomes. Yet, these compounds largely retain their inhibitory activity for bacterial ribosomes and show antibacterial activity. Our data indicate that 4'-O-substituted aminoglycosides possess increased selectivity towards bacterial ribosomes and little activity for any of the human drug-binding pockets.
Subject(s)
Aminoglycosides/chemistry , Aminoglycosides/pharmacology , Anti-Bacterial Agents/pharmacology , Aminoglycosides/therapeutic use , Animals , Anti-Bacterial Agents/therapeutic use , Base Sequence , Cell-Free System , Crystallography, X-Ray , Disease Models, Animal , Drug Interactions , Escherichia coli/drug effects , Escherichia coli/isolation & purification , Humans , Inhibitory Concentration 50 , Male , Mice , Microbial Sensitivity Tests , Molecular Sequence Data , Mycobacterium smegmatis/drug effects , Nucleic Acid Conformation , Protein Biosynthesis/drug effects , RNA, Ribosomal, 16S/chemistry , RNA, Ribosomal, 16S/genetics , Ribosomes/metabolism , Sepsis/drug therapy , Staphylococcus aureus/drug effectsABSTRACT
The furanosyl moiety (ring III) of C(6')-deoxyparomomycin and paromomycin was modified in search of aminoglycoside antibiotics with altered selectivity. The key intermediates were the N-Boc-protected derivative of C(6')-deoxyparomomycin and the benzylidene-protected paromomycin. Their H(2)C(5'')-OH group was oxidised with trichlorocyanuric acid or [bis(acetoxy)iodo]benzene in the presence of catalytic amounts of TEMPO to yield the corresponding aldehydes and acids, which were transformed into the protected alkoxy imines, amides and the amine. Standard deprotection gave the title compounds derived from C(6')-deoxyparomomycin and derived from paromomycin that proved less active than paromomycin and its C(6')-deoxy analogue.
Subject(s)
Paromomycin/analogs & derivatives , Paromomycin/chemical synthesis , RNA, Bacterial/chemistry , RNA, Ribosomal/chemistry , Mycobacterium smegmatis/drug effects , Oxidation-Reduction , Paromomycin/pharmacology , Ribosomes/drug effects , Structure-Activity RelationshipABSTRACT
The nitroaldol reaction of (1R)-8-phenylmenthyl glyoxylate (3b) with 1-nitro-1-phenylmethane (4) or with 1-nitro-2-phenylethane (13) led stereoselectively to adducts syn-2b and syn-12b, which were then transformed into the Taxotere side chain and (-)-bestatin hydrochloride in overall yields of 52% and 31%, respectively.
