Importance of the 6′‐Hydroxy Group and Its Configuration for Apramycin Activity

A series of apramycin derivatives was prepared and investigated for antibacterial activity and the ability to inhibit protein synthesis in cell‐free translation assays. The effect of various modifications at the 6′‐ and N7′‐positions on antiribosomal activity is discussed in terms of their influence on drug binding to specific residues in the decoding A‐site. These studies contribute to the development of a structure–activity relationship for the antibacterial activity of the apramycin class of aminoglycosides and to the future design and development of more active and less toxic antibiotics.

[1]  J. Schacht,et al.  The mitochondrion: A perpetrator of acquired hearing loss , 2013, Hearing Research.

[2]  J. Kondo,et al.  Identification of the molecular attributes required for aminoglycoside activity against Leishmania , 2013, Proceedings of the National Academy of Sciences.

[3]  I. Ojima.  Exploration of fluorine chemistry at the multidisciplinary interface of chemistry and biology. , 2013, The Journal of organic chemistry.

[4]  Colin Echeverría Aitken,et al.  The impact of aminoglycosides on the dynamics of translation elongation. , 2013, Cell reports.

[5]  M. A. King,et al.  Conformational analysis of fluorinated pyrrolidines using 19F-1H scalar couplings and heteronuclear NOEs. , 2012, Chemistry.

[6]  J. Xie,et al.  Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin , 2012, Proceedings of the National Academy of Sciences.

[7]  S. Alihodžić,et al.  Novel desosamine-modified 14- and 15-membered macrolides without antibacterial activity. , 2012, Bioorganic & medicinal chemistry letters.

[8]  S. Godefroy,et al.  N-demethylation of cyamemazine via non-classical Polonovski reaction and its conjugation to bovine serum albumin. , 2012, Bioorganic & medicinal chemistry letters.

[9]  J. Kondo.  A structural basis for the antibiotic resistance conferred by an A1408G mutation in 16S rRNA and for the antiprotozoal activity of aminoglycosides. , 2012, Angewandte Chemie.

[10]  Alexander A. Marchione,et al.  Investigation of the correlations between 19F and 1H NMR signals for various mono‐ and di‐substituted octafluoro[2.2]paracyclophanes , 2009, Magnetic resonance in chemistry : MRC.

[11]  S. Hobbie,et al.  Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity , 2008, Proceedings of the National Academy of Sciences.

[12]  A. Vasella,et al.  Synthesis and Evaluation of Paromomycin Derivatives Modified at C(4 , 2008 .

[13]  W. Hagmann,et al.  The many roles for fluorine in medicinal chemistry. , 2008, Journal of medicinal chemistry.

[14]  S. Hobbie,et al.  Mitochondrial deafness alleles confer misreading of the genetic code , 2008, Proceedings of the National Academy of Sciences.

[15]  S. Purser,et al.  Fluorine in medicinal chemistry. , 2008, Chemical Society reviews.

[16]  F. Diederich,et al.  Fluorine in Pharmaceuticals: Looking Beyond Intuition , 2007, Science.

[17]  A. Vasella,et al.  Engineering the rRNA decoding site of eukaryotic cytosolic ribosomes in bacteria , 2007, Nucleic acids research.

[18]  E. Westhof,et al.  Crystal structure of the Homo sapiens cytoplasmic ribosomal decoding site complexed with apramycin. , 2006, Angewandte Chemie.

[19]  Odile Eisenstein,et al.  An anion-dependent switch in selectivity results from a change of C-H activation mechanism in the reaction of an imidazolium salt with IrH5(PPh3)2. , 2005, Journal of the American Chemical Society.

[20]  Eric Westhof,et al.  Crystal structures of complexes between aminoglycosides and decoding A site oligonucleotides: role of the number of rings and positive charges in the specific binding leading to miscoding , 2005, Nucleic acids research.

[21]  T. Hermann,et al.  Molecular recognition by glycoside pseudo base pairs and triples in an apramycin-RNA complex. , 2005, Angewandte Chemie.

[22]  Eric Westhof,et al.  The Molecular Basis for A‐Site Mutations Conferring Aminoglycoside Resistance: Relationship between Ribosomal Susceptibility and X‐ray Crystal Structures , 2003, Chembiochem : a European journal of chemical biology.

[23]  B. Smart.  Fluorine substituent effects (on bioactivity) , 2001 .

[24]  V. Ramakrishnan,et al.  Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics , 2000, Nature.

[25]  W. Bauer.  Pulsed Field Gradient ‘Inverse’ HOESY Applied to the Isotope Pairs 1H,31P and 1H,7Li* , 1996 .

[26]  Mordechai Shohat,et al.  Mitochondrial ribosomal RNA mutation associated with both antibiotic–induced and non–syndromic deafness , 1993, Nature Genetics.

[27]  C. Chatgilialoglu.  Organosilanes as radical-based reducing agents in synthesis , 1992 .

[28]  W. Alborn,et al.  Comparison of aminoglycoside antibiotics with respect to uptake and lethal activity in Escherichia coli. , 1987, Journal of medicinal chemistry.

[29]  K. Akimoto,et al.  Total synthesis of aminoglycoside antibiotics, apramycin and saccharocin (KA-5685) , 1984 .

[30]  D. Dess,et al.  Readily accessible 12-I-5 oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones , 1983 .

[31]  H. Sagai,et al.  Saccharocin, a new aminoglycoside antibiotic. Fermentation, isolation, characterization and structural study. , 1983, The Journal of antibiotics.

[32]  T. Mori,et al.  A new aminoglycoside antibiotic, KA-5685. , 1983, The Journal of antibiotics.

[33]  H. Kawaguchi,et al.  Aminoglycoside antibiotics. XIV. Synthesis and activity of 6-O-(3-amino-3-deoxy-alpha-D-glucopyranosyl)-and 5-O-(beta-D-ribofuranosyl)apramycins. , 1981, The Journal of antibiotics.

[34]  N. D. Jones,et al.  Apramycin, a unique aminocyclitol antibiotic. , 1976, The Journal of organic chemistry.

[35]  R. Borch,et al.  Cyanohydridoborate anion as a selective reducing agent , 1971 .

[36]  E. W. Della.  Conformational analysis. Trifluoromethyl group , 1967 .

[37]  A. Vasella,et al.  Decoding and deafness: Two sides of a coin , 2011 .

[38]  Ramesh Krishnamurti,et al.  Synthetic methods and reactions. 141. Fluoride-induced trifluoromethylation of carbonyl compounds with trifluoromethyltrimethylsilane (TMS-CF3). A trifluoromethide equivalent , 1989 .

[39]  I. Ruppert,et al.  Die ersten CF3-substituierten organyl(chlor)silane , 1984 .

[40]  F. Hartley.  Eli Lilly , 1977, Nature.