Total syntheses and initial evaluation of [Ψ[C(═S)NH]Tpg⁴]vancomycin, [Ψ[C(═NH)NH]Tpg⁴]vancomycin, [Ψ[CH₂NH]Tpg⁴]vancomycin, and their (4-chlorobiphenyl)methyl derivatives: synergistic binding pocket and peripheral modifications for the glycopeptide antibiotics

Journal of the American Chemical Society
Akinori OkanoDale L Boger

Abstract

Full details of studies are disclosed on the total syntheses of binding pocket analogues of vancomycin bearing the peripheral L-vancosaminyl-1,2-D-glucosyl disaccharide that contain changes to a key single atom in the residue-4 amide (residue-4 carbonyl O → S, NH, H2) designed to directly address the underlying molecular basis of resistance to vancomycin. Also disclosed are studies piloting the late-stage transformations conducted on the synthetically more accessible C-terminus hydroxymethyl aglycon derivatives and full details of the peripheral chlorobiphenyl functionalization of all of the binding-pocket-modified vancomycin analogues designed for dual D-Ala-D-Ala/D-Ala-D-Lac binding. Their collective assessment indicates that combined binding pocket and chlorobiphenyl peripherally modified analogues exhibit a remarkable spectrum of antimicrobial activity (VSSA, MRSA, and VanA and VanB VRE) and impressive potencies against both vancomycin-sensitive and vancomycin-resistant bacteria (MICs = 0.06-0.005 and 0.5-0.06 μg/mL for the amidine and methylene analogues, respectively) and likely benefit from two independent and synergistic mechanisms of action, only one of which is dependent on D-Ala-D-Ala/D-Ala-D-Lac binding. Such analog...Continue Reading

References

Jan 1, 1989·The Journal of Antibiotics·R NagarajanA M Felty-Duckworth
Jul 21, 1988·The New England Journal of Medicine·R LeclercqP Courvalin
Jan 1, 1982·Pharmacology & Therapeutics·H R Perkins
Aug 1, 1993·The Journal of Antibiotics·R Nagarajan
Jun 1, 1996·The Journal of Antibiotics·R D CooperR C Thompson
Jan 1, 1997·Medicinal Research Reviews·A MalabarbaR C Thompson
Dec 15, 1996·Structure·M SchäferG M Sheldrick
Sep 16, 1998·Antimicrobial Agents and Chemotherapy·C G MarshallG D Wright
Jul 30, 1999·Angewandte Chemie·K C NicolaouN Winssinger
Sep 3, 1999·The Journal of Antimicrobial Chemotherapy·G CandianiF Parenti
Sep 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·I A Lessard, C T Walsh
Jul 18, 2001·Journal of the American Chemical Society·D L BogerJ J McAtee
Oct 2, 2001·Medicinal Research Reviews·D L Boger
Apr 5, 2002·Chembiochem : a European Journal of Chemical Biology·Roderich D Süssmuth
Jul 27, 2002·Annual Review of Microbiology·Timothy R Walsh, Robin A Howe
Aug 1, 2002·Journal of the American Chemical Society·Steven D DongDaniel Kahne
Feb 15, 2003·FEMS Microbiology Reviews·Norris E Allen, Thalia I Nicas
Apr 26, 2003·Proceedings of the National Academy of Sciences of the United States of America·Lan ChenDaniel Kahne
Jul 17, 2003·Journal of the American Chemical Society·Rishi K JainJonathan A Ellman
Aug 2, 2003·Journal of the American Chemical Society·Casey C McComasDale L Boger
Nov 11, 2003·Nature Biotechnology·Xun FuJon S Thorson
Nov 19, 2003·Bioorganic & Medicinal Chemistry Letters·J Kevin Judice, John L Pace
Apr 1, 2004·Journal of the American Chemical Society·Brendan M CrowleyDale L Boger
Apr 23, 2004·Drugs·Françoise Van BambekePaul M Tulkens
May 13, 2004·Journal of the American Chemical Society·Stefan WeistRoderich D Süssmuth
Feb 11, 2005·Chemical Reviews·Dan KahneChristopher Walsh
Feb 26, 2005·The Journal of Organic Chemistry·Jarugu Narasimha Moorthy, Nidhi Singhal
Apr 9, 2005·Organic Letters·Xun FuJon S Thorson
Jul 2, 2005·Angewandte Chemie·Desiree A ThayerChi-Huey Wong
Jul 28, 2005·Journal of the American Chemical Society·Markus OberthürDaniel Kahne
Nov 29, 2005·Natural Product Reports·Richard H BaltzStephen K Wrigley
Dec 3, 2005·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Patrice Courvalin

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Citations

Apr 25, 2017·Chemical Reviews·Akinori OkanoDale L Boger
Oct 11, 2016·Biochemical Pharmacology·Rustam Aminov
Mar 24, 2016·Angewandte Chemie·Mathieu F ChellatRainer Riedl
Oct 18, 2016·MedChemComm·Jed F Fisher, Shahriar Mobashery
Jul 12, 2017·ACS Chemical Biology·Clarissa C FornerisMohammad R Seyedsayamdost
Mar 8, 2018·Expert Opinion on Drug Discovery·David J Newman
Jun 14, 2017·Proceedings of the National Academy of Sciences of the United States of America·Steven L Castle
Jun 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Akinori OkanoDale L Boger
Apr 27, 2018·Angewandte Chemie·Clarissa C Forneris, Mohammad R Seyedsayamdost
Nov 26, 2015·Angewandte Chemie·Daohong LiaoXiaoguang Lei
Dec 6, 2017·Microbial Biotechnology·Carlos Molina-SantiagoDiego Romero
Jun 16, 2016·Chembiochem : a European Journal of Chemical Biology·Heather J JohnstonAlison N Hulme
Feb 20, 2018·ACS Medicinal Chemistry Letters·David J Newman
Sep 28, 2017·Chemical Reviews·Sean E RossiterWilliam M Wuest
Jul 29, 2020·ACS Central Science·Melissa A HardyRichmond Sarpong
Jan 25, 2018·ACS Infectious Diseases·Mark A T BlaskovichMatthew A Cooper
Apr 6, 2019·Journal of Medicinal Chemistry·Yasmeen AbouelhassanRobert W Huigens
Jan 31, 2019·ACS Chemical Biology·Nilkamal MahantaDouglas A Mitchell
Sep 5, 2020·Journal of the American Chemical Society·Maxwell J MooreDale L Boger
Nov 4, 2020·Accounts of Chemical Research·Zhi-Chen Wu, Dale L Boger

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