- Total Syntheses and Initial Evaluation of [Ψ[C(=S)NH]Tpg4]vancomycin, [Ψ[=NH)NH]Tpg4]vancomycin, [Ψ[CH2NH]Tpg4]vancomycin, and Their (4-Chlorobiphenyl)methyl Derivatives: Synergistic Binding Pocket and Peripheral Modifications for the Glycopeptide Antibiotics
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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 analogues are likely to display especially durable antibiotic activity that is not prone to rapidly acquired clinical resistance. (Chemical Equation Presented).
- Okano, Akinori,Nakayama, Atsushi,Wu, Kejia,Lindsey, Erick A.,Schammel, Alex W.,Feng, Yiqing,Collins, Karen C.,Boger, Dale L.
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- Enzymatic glycosylation of vancomycin aglycon: Completion of a total synthesis of vancomycin and N- and C-terminus substituent effects of the aglycon substrate
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Studies on the further development of the sequential glycosylations of the vancomycin aglycon catalyzed by the glycosyltransferases GtfE and GtfD and the observation of unusual, perhaps unexpected, aglycon substrate substituent effects on the rate and eff
- Nakayama, Atsushi,Okano, Akinori,Feng, Yiqing,Collins, James C.,Collins, Karen C.,Walsh, Christopher T.,Boger, Dale L.
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- Selective Cleavage of Vancosamine, Glucose, and N-Methyl-leucine from Vancomycin and Related Antibiotics
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Reaction of vancomycin and related antibiotics with trifluoroacetic acid at -15 deg C for 40 h selectively cleaved the amino sugar vancosamine; the second sugar, glucose, was removed by reaction with trifluoroacetic acid at 50 deg C for 3 h, and the N-terminal leucine moiety was cleaved using the Edman degradation procedure.
- Nagarajan, Ramakrishnan,Schabel, Amelia A.
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- Impurity Identification and Scale-Up of a Novel Glycopeptide Antibiotic
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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.
- Guan, Dongliang,Huang, Wei,Jiao, Shang,Li, Jian,Liu, Bo,Shi, Weiwei,Tang, Feng,Xu, Lili
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p. 2390 - 2402
(2021/11/01)
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- METHODS OF USING SEMI-SYNTHETIC GLYCOPEPTIDES AS ANTIBACTERIAL AGENTS
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Methods of using semi-synthetic glycopeptides of formula I-XIV having antibacterial activity are described.
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Page/Page column 51
(2011/11/30)
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- NOVEL SEMI-SYNTHETIC GLYCOPEPTIDES AS ANTIBACTERIAL AGENTS
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Semi-synthetic glycopeptides having antibacterial activity are described, in particular, the semi-synthetic glycopeptides described herein are made by chemical modification of a glycopeptide (Compound A, Compound B, Compound H or Compound C) or monosaccharide made by hydrolyzing the disaccharide moiety of the amino acid-4 of the parent glycopeptide in acidic medium to give the amino acid-4 monosaccharide; conversion of the monosaccharide to the amino-sugar derivative; acylation of the amino substituent on the amino acid-4 amino-substituted sugar moiety on these scaffolds with certain acyl groups; and conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides. Key reaction is the treatment of properly protected intermediate compound with isocyanate or carrying a Hofmann degradation of the primary amide of the 3rd amino acid asparagines with phenyl-bis-trifluoroacetate to give the primary amine. Also provided are methods for the synthesis of the compounds, pharmaceutical compositions containing the compounds, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections.
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Page/Page column 67-68
(2009/08/14)
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- SEMI-SYNTHETIC GLYCOPEPTIDES WITH ANTIBACTERIAL ACTIVITY
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Semi- synthetic glycopeptides having antibacterial activity are described, in particular, the semi-synthetic glycopeptides described hereins are made by subjecting the a glycopeptide (Compound A, Compound B, COMPOUND H or Compound C) in acidic medium to hydrolyze the disaccharide moiety of the amino acid-4 of the parent glycopeptide to give the amino acid-4 monosaccharide; temporary protection of the amino grouρ(s); conversion of the monosaccharide to the amino-sugar derivative; acylation of the amino substituent on the amino acid-4 amino-substituted sugar moiety on these scaffolds with certain acyl groups; conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides and removal of the tempory aimo protection grouρ(s). Also provided are methods for the synthesis of the compounds, pharmaceutical compositions containing the compounds, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections.
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Page/Page column 58
(2009/01/20)
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- Glycosylation of glycopeptides: A comparison of chemoenzymatic and chemical methods
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Glycosylating complex molecules remains a major synthetic challenge, making it hard to explore carbohydrate diversity in biologically active glycosylated natural products and their derivatives. In this paper we compare the efficiency of chemical and enzym
- Leimkuhler, Catherine,Chen, Zhong,Kruger, Ryan G.,Oberthuer, Markus,Lu, Wei,Walsh, Christopher T.,Kahne, Daniel
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p. 599 - 603
(2007/10/03)
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- A systematic investigation of the synthetic utility of glycopeptide glycosyltransferases
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Glycosyltransferases involved in the biosynthesis of bacterial secondary metabolites may be useful for the generation of sugar-modified analogues of bioactive natural products. Some glycosyltransferases have relaxed substrate specificity, and it has been assumed that promiscuity is a feature of the class. As part of a program to explore the synthetic utility of these enzymes, we have analyzed the substrate selectivity of glycosyltransferases that attach similar 2-deoxy-L-sugars to glycopeptide aglycons of the vancomycin-type, using purified enzymes and chemically synthesized TDP β-2-deoxy-L-sugar analogues. We show that while some of these glycopeptide glycosyltransferases are promiscuous, others tolerate only minor modifications in the substrates they will handle. For example, the glycosyltransferases GtfC and GtfD, which transfer 4-epi-L-vancosamine and L-vancosamine to C-2 of the glucose unit of vancomycin pseudoaglycon and chloroorienticin B, respectively, show moderately relaxed donor substrate specificities for the glycosylation of their natural aglycons. In contrast, GtfA, a transferase attaching 4-epi-L-vancosamine to a benzylic position, only utilizes donors that are closely related to its natural TDP sugar substrate. Our data also show that the spectrum of donors utilized by a given enzyme can depend on whether the natural acceptor or an analogue is used, and that GtfD is the most versatile enzyme for the synthesis of vancomycin analogues.
- Oberthuer, Markus,Leimkuhler, Catherine,Kruger, Ryan G.,Lu, Wei,Walsh, Christopher T.,Kahne, Daniel
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p. 10747 - 10752
(2007/10/03)
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- Function of the amino sugar and N-terminal amino acid of the antibiotic vancomycin in its complexation with cell wall peptides
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Four N-acetylated derivatives of vancomycin (1) were prepared: the derivative at the N-terminus (2, NAcV), the N-acetyl derivative on the vancosamine residue (3, N'AcV), the N,N'-bis derivative (4, DiAcV), and the N-terminal derivative of the aglycon (6,
- Kannan,Harris,Harris,Waltho,Skelton,Williams
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p. 2946 - 2953
(2007/10/02)
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