Synthesis and antibacterial activity of doxycycline neoglycosides.

A set of 37 doxycycline neoglycosides were prepared, mediated via a C-9 alkoxyamino-glycyl-based spacer reminiscent of that of tigecycline. Subsequent in vitro antibacterial assays against representative drug-resistant Gram negative and Gram positive strains revealed a sugar-dependent activity profile and one doxycycline neoglycoside, the 2'-amino-α-D-glucoside conjugate, to rival that of the parent pharmacophore. In contrast, the representative tetracycline-susceptible strain E. coli 25922 was found to be relatively responsive to a range of doxycycline neoglycosides. This study also extends the use of aminosugars in the context of neoglycosylation via a simple two-step strategy anticipated to be broadly applicable for neoglycorandomization.

[1]  Derek K. Rogalsky,et al.  Amphimedosides A-C: synthesis, chemoselective glycosylation, and biological evaluation. , 2013, The Journal of organic chemistry.

[2]  T. Loh,et al.  Organoindium reagents: the preparation and application in organic synthesis. , 2013, Chemical reviews.

[3]  J. Thorson,et al.  Natural product disaccharide engineering through tandem glycosyltransferase catalysis reversibility and neoglycosylation. , 2012, Organic letters.

[4]  G. Phillips,et al.  The structural biology of enzymes involved in natural product glycosylation. , 2012, Natural product reports.

[5]  I. André,et al.  Sucrose analogs: an attractive (bio)source for glycodiversification. , 2012, Natural product reports.

[6]  Hien M. Nguyen,et al.  Recent Advances in Transition Metal-Catalyzed Glycosylation. , 2012, ACS catalysis.

[7]  D. Trauner,et al.  Stereoselective total syntheses of herbicidin C and aureonuclemycin through late-stage glycosylation. , 2012, Angewandte Chemie.

[8]  J. Thorson,et al.  Enhancement of cyclopamine via conjugation with nonmetabolic sugars. , 2012, Organic letters.

[9]  J. M. Langenhan,et al.  Synthesis and biological evaluation of RON-neoglycosides as tumor cytotoxins. , 2011, Carbohydrate research.

[10]  Chi‐Huey Wong,et al.  Toward automated oligosaccharide synthesis. , 2011, Angewandte Chemie.

[11]  J. Thorson,et al.  Enzymatic methods for glyco(diversification/randomization) of drugs and small molecules. , 2011, Natural product reports.

[12]  Javier González‐Sabín,et al.  Regioselective enzymatic acylation of complex natural products: expanding molecular diversity. , 2011, Chemical Society reviews.

[13]  J. Thorson,et al.  Warfarin Glycosylation Invokes a Switch from Anticoagulant to Anticancer Activity , 2011, ChemMedChem.

[14]  Chi-Huey Wong,et al.  Enzymes in the synthesis of glycoconjugates. , 2011, Chemical reviews.

[15]  J. Thorson,et al.  Glycosyloxyamine Neoglycosylation: A Model Study Using Calicheamicin , 2011, ChemMedChem.

[16]  Xiao-yi Xiao,et al.  Synthesis and Antibacterial Activity of Pentacyclines: A Novel Class of Tetracycline Analogs , 2011, Journal of medicinal chemistry.

[17]  Xiao-yi Xiao,et al.  8-Azatetracyclines: Synthesis and Evaluation of a Novel Class of Tetracycline Antibacterial Agents , 2011, Journal of medicinal chemistry.

[18]  L. Cipolla,et al.  Carbohydrate-based bioactive compounds for medicinal chemistry applications. , 2011, Mini reviews in medicinal chemistry.

[19]  J. Thorson,et al.  Assessment of chemoselective neoglycosylation methods using chlorambucil as a model. , 2010, Journal of medicinal chemistry.

[20]  José Ramón Suárez,et al.  Nonafluorobutanesulfonyl Azide: A Shelf-Stable Diazo Transfer Reagent for the Synthesis of Azides from Primary Amines , 2010 .

[21]  K. McConeghy,et al.  In vitro activity of tigecycline in combination with gentamicin against biofilm-forming Staphylococcus aureus. , 2010, Diagnostic microbiology and infectious disease.

[22]  M. John-Aryankalayil,et al.  Doxycycline's effect on ocular angiogenesis: an in vivo analysis. , 2010, Ophthalmology.

[23]  M. Carrasco,et al.  Synthesis of aminooxy and N-alkylaminooxy amines for use in bioconjugation. , 2010, The Journal of organic chemistry.

[24]  Derek K. Rogalsky,et al.  A Direct Comparison of the Anticancer Activities of Digitoxin MeON-Neoglycosides and O-Glycosides: Oligosaccharide Chain Length-Dependent Induction of Caspase-9-Mediated Apoptosis. , 2010, ACS medicinal chemistry letters.

[25]  J. Shieh,et al.  Activation of c‐Jun N‐terminal kinase is essential for mitochondrial membrane potential change and apoptosis induced by doxycycline in melanoma cells , 2010, British journal of pharmacology.

[26]  D. Crich.  Mechanism of a chemical glycosylation reaction. , 2010, Accounts of chemical research.

[27]  M. Saux,et al.  Pharmacokinetics of doxycycline polyphosphate after oral multiple dosing in humans , 2010, European Journal of Drug Metabolism and Pharmacokinetics.

[28]  Kenji Watanabe,et al.  Biochemical analysis of the biosynthetic pathway of an anticancer tetracycline SF2575. , 2009, Journal of the American Chemical Society.

[29]  D. Raoult,et al.  Therapeutic impact of the correlation of doxycycline serum concentrations and the decline of phase I antibodies in Q fever endocarditis. , 2009, The Journal of antimicrobial chemotherapy.

[30]  R. Schmidt,et al.  New principles for glycoside-bond formation. , 2009, Angewandte Chemie.

[31]  P. Arya,et al.  Advances in solution- and solid-phase synthesis toward the generation of natural product-like libraries. , 2009, Chemical reviews.

[32]  J. Thorson,et al.  Enhancing the divergent activities of betulinic acid via neoglycosylation. , 2009, Organic letters.

[33]  C. Thibodeaux,et al.  Natural-product sugar biosynthesis and enzymatic glycodiversification. , 2008, Angewandte Chemie.

[34]  L. Peterson.  A review of tigecycline--the first glycylcycline. , 2008, International journal of antimicrobial agents.

[35]  J. Hylands.  Tigecycline: a new antibiotic. , 2008, Intensive & critical care nursing.

[36]  M. Santagati,et al.  Evaluation of the in vitro activity of tigecycline against multiresistant Gram-positive cocci containing tetracycline resistance determinants. , 2008, International journal of antimicrobial agents.

[37]  J. M. Langenhan,et al.  Modifying the glycosidic linkage in digitoxin analogs provides selective cytotoxins. , 2008, Bioorganic & medicinal chemistry letters.

[38]  C. Edmiston,et al.  Model for antibiotic optimization via neoglycosylation: synthesis of liponeoglycopeptides active against VRE. , 2007, Journal of the American Chemical Society.

[39]  D. Gin,et al.  Chemical glycosylation in the synthesis of glycoconjugate antitumour vaccines , 2007, Nature.

[40]  C. Thibodeaux,et al.  Unusual sugar biosynthesis and natural product glycodiversification , 2007, Nature.

[41]  E. Bouza,et al.  In vitro activity of tigecycline against clinical isolates of Acinetobacter baumannii and Stenotrophomonas maltophilia. , 2007, The Journal of antimicrobial chemotherapy.

[42]  C. Lilley,et al.  Using or abusing: viruses and the cellular DNA damage response. , 2007, Trends in microbiology.

[43]  Ronald N. Jones,et al.  Tigecycline (GAR-936) activity against Streptococcus gallolyticus (bovis) and viridans group streptococci. , 2007, Diagnostic microbiology and infectious disease.

[44]  M. Garrison,et al.  In vitro activity of tigecycline against quinolone-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. , 2007, International journal of antimicrobial agents.

[45]  David G Lalloo,et al.  UK malaria treatment guidelines. , 2007, The Journal of infection.

[46]  A. Fraise.  Tigecycline: the answer to beta-lactam and fluoroquinolone resistance? , 2006, The Journal of infection.

[47]  James A. Watson,et al.  Colchicine glycorandomization influences cytotoxicity and mechanism of action. , 2006, Journal of the American Chemical Society.

[48]  De-Quan Li,et al.  Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye. , 2006, Experimental eye research.

[49]  Joseph L. DeRisi,et al.  Tetracyclines Specifically Target the Apicoplast of the Malaria Parasite Plasmodium falciparum , 2006, Antimicrobial Agents and Chemotherapy.

[50]  H. B. Fung,et al.  Tigecycline: a glycylcycline antimicrobial agent. , 2006, Clinical therapeutics.

[51]  G. Petrikkos,et al.  In vitro activities of tigecycline against recently isolated Gram-negative anaerobic bacteria in Greece, including metronidazole-resistant strains. , 2006, Diagnostic microbiology and infectious disease.

[52]  J. Thorson,et al.  Enzymatic tools for engineering natural product glycosylation. , 2006, Current opinion in chemical biology.

[53]  T. Rush,et al.  Functional, Biophysical, and Structural Bases for Antibacterial Activity of Tigecycline , 2006, Antimicrobial Agents and Chemotherapy.

[54]  P. Petersen,et al.  Synthesis and antibacterial activity of 9-substituted minocycline derivatives. , 2006, Bioorganic & medicinal chemistry letters.

[55]  H. Kondo,et al.  Molecular design of glycoprotein mimetics: glycoblotting by engineered proteins with an oxylamino-functionalized amino acid residue. , 2005, Chemistry.

[56]  D. Livermore.  Tigecycline: what is it, and where should it be used? , 2005, The Journal of antimicrobial chemotherapy.

[57]  J. O'Connell,et al.  Tigecycline MIC Testing by Broth Dilution Requires Use of Fresh Medium or Addition of the Biocatalytic Oxygen-Reducing Reagent Oxyrase To Standardize the Test Method , 2005, Antimicrobial Agents and Chemotherapy.

[58]  D. Felmingham.  Tigecycline – The First Glycylcycline to Undergo Clinical Development: An Overview of In Vitro Activity Compared to Tetracycline , 2005, Journal of chemotherapy.

[59]  D. Raoult,et al.  Correlation between Ratio of Serum Doxycycline Concentration to MIC and Rapid Decline of Antibody Levels during Treatment of Q Fever Endocarditis , 2005, Antimicrobial Agents and Chemotherapy.

[60]  Achim Hoerauf,et al.  Macrofilaricidal activity after doxycycline treatment of Wuchereria bancrofti: a double-blind, randomised placebo-controlled trial , 2005, The Lancet.

[61]  D. Siegel,et al.  Synthesis of (-)-tetracycline. , 2005, Journal of the American Chemical Society.

[62]  Andrew G Myers,et al.  A Convergent Enantioselective Route to Structurally Diverse 6-Deoxytetracycline Antibiotics , 2005, Science.

[63]  M. Roberts.  Update on acquired tetracycline resistance genes. , 2005, FEMS microbiology letters.

[64]  D. Nathwani.  Tigecycline: clinical evidence and formulary positioning. , 2005, International journal of antimicrobial agents.

[65]  E. Rubinstein,et al.  Tigecycline , 2012, Drugs.

[66]  Carlos Matute,et al.  Neuroprotection by tetracyclines. , 2004, Trends in pharmacological sciences.

[67]  W. Hillen,et al.  Comparison of tetracycline and tigecycline binding to ribosomes mapped by dimethylsulphate and drug-directed Fe2+ cleavage of 16S rRNA. , 2004, The Journal of antimicrobial chemotherapy.

[68]  L. Golub,et al.  Subantimicrobial dose doxycycline efficacy as a matrix metalloproteinase inhibitor in chronic periodontitis patients is enhanced when combined with a non-steroidal anti-inflammatory drug. , 2004, Journal of periodontology.

[69]  J. Karlowsky,et al.  The Glycylcyclines , 2004, Drugs.

[70]  M. Carrasco,et al.  A versatile set of aminooxy amino acids for the synthesis of neoglycopeptides. , 2003, The Journal of organic chemistry.

[71]  M. Gobbo,et al.  Opioid peptides: synthesis and biological properties of [(N gamma-glucosyl,N gamma-methoxy)-alpha, gamma-diamino-(S)-butanoyl]4-deltorphin-1-neoglycopeptide and related analogues. , 2003, Organic & biomolecular chemistry.

[72]  P. Hawkins,et al.  Versatile and facile synthesis of diverse semisynthetic tetracycline derivatives via Pd-catalyzed reactions. , 2003, The Journal of organic chemistry.

[73]  A. Hoerauf,et al.  Doxycycline as a novel strategy against bancroftian filariasis—depletion of Wolbachia endosymbionts from Wuchereria bancrofti and stop of microfilaria production , 2003, Medical Microbiology and Immunology.

[74]  H. Myszka,et al.  Synthesis and induction of apoptosis in B cell chronic leukemia by diosgenyl 2-amino-2-deoxy-beta-D-glucopyranoside hydrochloride and its derivatives. , 2003, Carbohydrate research.

[75]  I. Serafimova,et al.  Synthesis of N-Fmoc-O- (N'-Boc-N'-methyl)-aminohomoserine, an amino acid for the facile preparation of neoglycopeptides. , 2003, The Journal of organic chemistry.

[76]  D. Koza,et al.  Synthesis and biological evaluation of 9-substituted tetracycline derivatives. , 2002, Bioorganic & medicinal chemistry letters.

[77]  S. Hengel,et al.  Synthesis of neoglycopeptides by chemoselective reaction of carbohydrates with peptides containing a novel N′-methyl-aminooxy amino acid , 2002 .

[78]  I. Chopra.  New developments in tetracycline antibiotics: glycylcyclines and tetracycline efflux pump inhibitors. , 2002, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[79]  J. Ridet,et al.  Recombinant proteins for neurodegenerative diseases: the delivery issue , 2001, Trends in Neurosciences.

[80]  Marilyn Roberts,et al.  Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance , 2001, Microbiology and Molecular Biology Reviews.

[81]  B. Imperiali,et al.  Asparagine surrogates for the assembly of N-linked glycopeptide mimetics by chemoselective ligation , 2001 .

[82]  V. Ramakrishnan,et al.  The Structural Basis for the Action of the Antibiotics Tetracycline, Pactamycin, and Hygromycin B on the 30S Ribosomal Subunit , 2000, Cell.

[83]  Y. Chernajovsky,et al.  A novel doxycycline inducible autoregulatory plasmid which displays ‘on’/‘off’ regulation suited to gene therapy applications , 2000, Gene Therapy.

[84]  H. Spaink,et al.  Chemical synthesis of N-acetylglucosamine derivatives and their use as glycosyl acceptors by the Mesorhizobium loti chitin oligosaccharide synthase NodC , 1999 .

[85]  P. Petersen,et al.  Synthesis and structure-activity relationship of novel glycylcycline derivatives leading to the discovery of GAR-936. , 1999, Bioorganic & medicinal chemistry letters.

[86]  N. Jacobus,et al.  In Vitro and In Vivo Antibacterial Activities of a Novel Glycylcycline, the 9-t-Butylglycylamido Derivative of Minocycline (GAR-936) , 1999, Antimicrobial Agents and Chemotherapy.

[87]  J. Mallet,et al.  A single adenovirus vector mediates doxycycline-controlled expression of tyrosine hydroxylase in brain grafts of human neural progenitors , 1999, Nature Biotechnology.

[88]  R. Fife,et al.  Effects of Doxycycline on Cancer Cells in Vitro and in Vivo , 1998, Advances in dental research.

[89]  S. Prusiner,et al.  Doxycycline control of prion protein transgene expression modulates prion disease in mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[90]  S. Trapnell,et al.  The pharmacokinetic profile of a biodegradable controlled-release delivery system containing doxycycline compared to systemically delivered doxycycline in gingival crevicular fluid, saliva, and serum. , 1998, Journal of periodontology.

[91]  M. Ammirati,et al.  Glycylcyclines bind to the high-affinity tetracycline ribosomal binding site and evade Tet(M)- and Tet(O)-mediated ribosomal protection , 1996, Antimicrobial Agents and Chemotherapy.

[92]  T. Salo,et al.  In vivo inhibition of human neutrophil collagenase (MMP‐8) activity during long‐term combination therapy of doxycycline and non‐steroidal anti‐inflammatory drugs (NSAID) in acute reactive arthritis , 1994, Clinical and experimental immunology.

[93]  P. Petersen,et al.  "Glycylcyclines". 3. 9-Aminodoxycyclinecarboxamides. , 1994, Journal of medicinal chemistry.

[94]  S. Tanida,et al.  New naphthacenecarboxamide antibiotics, TAN-1518 A and B, have inhibitory activity against mammalian DNA topoisomerase I. , 1994, The Journal of antibiotics.

[95]  J. Bloom,et al.  Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines. , 1994, Journal of medicinal chemistry.

[96]  M. Martens,et al.  Multicenter Randomized Trial of Ofloxacin Versus Cefoxitin and Doxycycline in Outpatient Treatment of Pelvic Inflammatory Disease , 1993 .

[97]  W. Trejo,et al.  Dactylocyclines: novel tetracycline glycosides active against tetracycline-resistant bacteria , 1993 .

[98]  J. S. Wells,et al.  Dactylocyclines, novel tetracycline derivatives produced by a Dactylosporangium sp. I. Taxonomy, production, isolation and biological activity. , 1992, The Journal of antibiotics.

[99]  N. Andersen,et al.  Dactylocyclines, novel tetracycline derivatives produced by a Dactylosporangium sp. II. Structure elucidation. , 1992, The Journal of antibiotics.

[100]  Zhu Shizheng.  Synthesis of fluoroalkanesulfonyl azides and their reactions as fluoroalkanesulfonyl nitrene precursors , 1992 .

[101]  R. Sweet,et al.  Treatment of hospitalized patients with acute pelvic inflammatory disease: comparison of cefotetan plus doxycycline and cefoxitin plus doxycycline. , 1988, American journal of obstetrics and gynecology.

[102]  C. Warren,et al.  235. New syntheses of 2-amino-2-deoxy-D-allose (D-allosamine), 2-amino-2-deoxy-D-ribose (D-ribosamine), and 2-amino-2-deoxy-D-xylose (D-xylosamine) , 1965 .

[103]  M. Wolfrom,et al.  A Synthesis of Streptidine1 , 1950 .