82198-76-3Relevant academic research and scientific papers
Attempted introduction of a fourth amide NH into the carboxylate-binding pocket of glycopeptide antibiotics
Goerlitzer, Jochen,Gale, Thomas F.,Williams, Dudley H.
, p. 3253 - 3257 (1999)
We report the synthesis of a novel derivative of the glycopeptide antibiotic vancomycin, modified at the N-terminus. This incorporates a fourth amide NH into the antibiotic, at the position which was formerly the N-terminus of the antibiotic-binding pocke
Thermal atropisomerism of aglucovancomycin derivatives: Preparation of (M,M,M)- and (P,M,M)-aglucovancomycins
Boger, Dale L.
, p. 8920 - 8926 (1998)
The degradation of vancomycin to a series of aglucovancomycin derivatives containing modifications in key functional groups and a study of their thermal atropisomerism are detailed. In all of the cases, selective isomerism of the DE ring system atropisomers was observed under conditions where the CD and AB stereochemistries were unaffected. Competitive retro aldol ring cleavage of the CD and DE ring systems (CD > DE) was observed but could be minimized by the choice of solvent and thermal conditions (DE ring system) or precluded by alcohol protection (CD ring system). Similarly, competitive main chain succinimide formation through the loss of ammonia from the Asn residue could be minimized by the choice of thermal conditions or prevented by carboxamide protection. Resynthesis of natural aglucovancomycin, (M,M,M)-2, and its unnatural DE atropisomer (P,M,M)-2 from 6 are described. The comparative antimicrobial activity of the key derivatives and their unnatural DE ring system P-diastereomers are disclosed.
Impurity Identification and Scale-Up of a Novel Glycopeptide Antibiotic
Guan, Dongliang,Huang, Wei,Jiao, Shang,Li, Jian,Liu, Bo,Shi, Weiwei,Tang, Feng,Xu, Lili
, p. 2390 - 2402 (2021/11/01)
A variety of novel glycopeptide antibiotics have been developed to combat the drug-resistant bacterial strains. Previously, we reported a series of vancomycin derivatives that are modified with lipid tails and extra sugars. SM-V-61, as one of the vancomycin analogues with a trifluoromethyl-biphenyl fragment and galactose, showed enhanced antibacterial activity, improved PK/PD, better water solubility, and safety. However, the deficient synthetic procedure, lower yield, and complicated impurities hindered the further development of the drug candidate SM-V-61. Herein, we reported a further study on SM-V-61 impurity analysis and process optimization. We first synthesized and identified a variety of impurities and established the analytical method for quality analysis and control of SM-V-61. Based on the defined analytical method, we optimized the synthetic procedure for SM-V-61 and operated the synthesis on 30-40 and 500-600 g scales in the laboratory and manufacturing workshop, respectively.
Next-Generation Total Synthesis of Vancomycin
Boger, Dale L.,Cai, Yu,Jamin Keith, D.,Mogi, Yuzo,Moore, Maxwell J.,Qu, Shiwei,Tan, Ceheng
supporting information, p. 16039 - 16050 (2020/10/02)
A next-generation total synthesis of vancomycin aglycon is detailed that was achieved in 17 steps (longest linear sequence, LLS) from the constituent amino acid subunits with kinetically controlled diastereoselective introduction of all three elements of atropisomerism. In addition to new syntheses of three of the seven amino acid subunits, highlights of the approach include a ligand-controlled atroposelective one-pot Miyaura borylation-Suzuki coupling sequence for introduction of the AB biaryl axis of chirality (>20:1 dr), an essentially instantaneous and scalable macrolactamization of the AB ring system nearly free of competitive epimerization (>30:1 dr), and two room-temperature atroposelective intramolecular SNAr cyclizations for sequential CD (8:1 dr) and DE ring closures (14:1 dr) that benefit from both preorganization by the preformed AB ring system and subtle substituent effects. Combined with a protecting group free two-step enzymatic glycosylation of vancomycin aglycon, this provides a 19-step total synthesis of vancomycin. The approach paves the way for large-scale synthetic preparation of pocket-modified vancomycin analogues that directly address the underlying mechanism of resistance to vancomycin.
Vancomycin-Dependent Response in Live Drug-Resistant Bacteria by Metabolic Labeling
Pidgeon, Sean E.,Pires, Marcos M.
supporting information, p. 8839 - 8843 (2017/07/17)
The surge in drug-resistant bacterial infections threatens to overburden healthcare systems worldwide. Bacterial cell walls are essential to bacteria, thus making them unique targets for the development of antibiotics. We describe a cellular reporter to directly monitor the phenotypic switch in drug-resistant bacteria with temporal resolution. Vancomycin-resistant enterococci (VRE) escape the bactericidal action of vancomycin by chemically modifying their cell-wall precursors. A synthetic cell-wall analogue was developed to hijack the biosynthetic rewiring of drug-resistant cells in response to antibiotics. Our study provides the first in vivo VanX reporter agent that responds to cell-wall alteration in drug-resistant bacteria. Cellular reporters that reveal mechanisms related to antibiotic resistance can potentially have a significant impact on the fundamental understanding of cellular adaption to antibiotics.
Lipophilic vancomycin aglycon dimer with high activity against vancomycin-resistant bacteria
Yarlagadda, Venkateswarlu,Sarkar, Paramita,Manjunath, Goutham B.,Haldar, Jayanta
supporting information, p. 5477 - 5480 (2015/11/18)
Antibiotic-resistant superbugs such as vancomycin-resistant Enterococci (VRE) and Staphylococci have become a major global health hazard. To address this issue, we synthesized vancomycin aglycon dimers to systematically probe the impact of a linker on biological activity. A dimer having a pendant lipophilic moiety in the linker showed ～300-fold more activity than vancomycin against VRE. The high activity of the compound is attributed to its enhanced binding affinity to target peptides which resulted in improved peptidoglycan (cell wall) biosynthesis inhibition. Therefore, our studies suggest that these compounds, prepared by using facile synthetic methodology, can be used to combat vancomycin-resistant bacterial infections.
Structure-activity relationship studies of a series of antiviral and antibacterial aglycon derivatives of the glycopeptide antibiotics vancomycin, eremomycin, and dechloroeremomycin
Printsevskaya, Svetlana S.,Solovieva, Svetlana E.,Olsufyeva, Eugenia N.,Mirchink, Elena P.,Isakova, Elena B.,De Clercq, Erik,Balzarini, Jan,Preobrazhenskaya, Maria N.
, p. 3885 - 3890 (2007/10/03)
N-Adamantyl-1)methyl, N-(adamantyl-2), and N-(ω-aminodecyl) amides of vancomycin, eremomycin, and dechloroeremomycin aglycons and their des-(N-Me-D-Leu) derivatives were synthesized and their antibacterial and anti-HIV activities were investigated. Carbox
A new and improved method for deglycosidation of glycopeptide antibiotics exemplified with vancomycin, ristocetin, and ramoplanin
Wanner, Jutta,Tang, Datong,McComas, Casey C.,Crowley, Brendan M.,Jiang, Wanlong,Moss, Jason,Boger, Dale L.
, p. 1169 - 1173 (2007/10/03)
A general method for the deglycosidation of glycopeptide antibiotics has been developed. Treatment of vancomycin, ristocetin, and ramoplanin with anhydrous HF results in efficient cleavage of the sugars to provide the corresponding aglycons in high yield.
Expression and assay of an N-methyltransferase involved in the biosynthesis of a vancomycin group antibiotic
O'Brien, Dominic P.,Kirkpatrick, Peter N.,O'Brien, Simon W.,Staroske, Thomas,Richardson, Timothy I.,Evans, David A.,Hopkinson, Andrew,Spencer, Jonathan B.,Williams, Dudley H.
, p. 103 - 104 (2007/10/03)
An N-methyltransferase responsible for methylating the N-terminal leucine of a vancomycin group antibiotic has been expressed, and its activity assayed against a series of putative vancomycin precursors.
Total synthesis of vancomycin - Part 3: Synthesis of the aglycon
Nicolaou,Koumbis, Alexandros E.,Takayanagi, Masaru,Natarajan, Swaminathan,Jain, Nareshkumar F.,Bando, Toshikazu,Li, Hui,Hughes, Robert
, p. 2622 - 2647 (2007/10/03)
The total synthesis of the vancomycin aglycon (2, Figure 1) is described. Construction of the key intermediate, tricyclic triazene 3 a (Figure 2), was accomplished in the order C-O-D →AB/C-O-D →AB/C-O-D/D-O-E. The C-O-D ring system 18a (Scheme 2) was form
