Glycoside cleavage reactions on erythromycin A. Preparation of erythronolide A

LeMahieu, Ronald A.; Carson, M.; Kierstead, R. W.; Fern, L. M.; Grünberg, E.

doi:10.1021/jm00255a009

Cited by 56 publications

(18 citation statements)

References 5 publications

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“…AZM 1: The removal of the cladinose of AZM followed a previously described procedure . Briefly, AZM (6.67 mmol) was dissolved into 200 mL of methanol containing 1% of conc.…”

Section: Methodsmentioning

confidence: 99%

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

et al. 2019

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Summary Introduction Azithromycin (AZM) and other macrolide antibiotics are applied as immunomodulatory treatments for CNS disorders. The immunomodulatory and antibiotic properties of AZM are purportedly independent. Aims To improve the efficacy and reduce antibiotic resistance risk of AZM‐based therapies, we evaluated the immunomodulatory and neuroprotective properties of novel AZM derivatives. We semisynthetically prepared derivatives by altering sugar moieties established as important for inhibiting bacterial protein synthesis. Bone marrow‐derived macrophages (BMDMs) were stimulated in vitro with proinflammatory, M1, stimuli (LPS + INF‐gamma) with and without derivative costimulation. Pro‐ and anti‐inflammatory cytokine production, IL‐12 and IL‐10, respectively, was quantified using ELISA. Neuron culture treatment with BMDM supernatant was used to assess derivative neuroprotective potential. Results Azithromycin and some derivatives increased IL‐10 and reduced IL‐12 production of M1 macrophages. IL‐10/IL‐12 cytokine shifts closely correlated with the ability of AZM and derivatives to mitigate macrophage neurotoxicity. Conclusions Sugar moieties that bind bacterial ribosomal complexes can be modified in a manner that retains AZM immunomodulation and neuroprotection. Since the effects of BMDMs in vitro are predictive of CNS macrophage responses, our results open new therapeutic avenues for managing maladaptive CNS inflammation and support utilization of IL‐10/12 cytokine profiles as indicators of macrophage polarization and neurotoxicity.

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“…AZM 1: The removal of the cladinose of AZM followed a previously described procedure . Briefly, AZM (6.67 mmol) was dissolved into 200 mL of methanol containing 1% of conc.…”

Section: Methodsmentioning

confidence: 99%

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

et al. 2019

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“…According to the generated data, 1 degrades in acidic environment (pH 2–3) to only one degradant 2 () in less than 24 h. This process is temperature dependent in term of increase of quantity of degradant with elevation of temperature (3.7% at 5°C, 26.2°C at 25°C, and 99.3% at 50°C). Decomposition pathway includes acid‐catalyzed hydrolysis of the cladinose sugar glycosidic bond, leading to a decladinosyl derivative and is characteristic for 15‐membered azalides as a result of stabilization of aglycone ring by methyl‐substituted nitrogen at the 9a position 24–26. At pH values 5 to 6 and temperature 5°C and 25°C, 1 exhibits significant stability for up to 1 week, whereas at 50°C, it is stable up to 24 h. Degradation of 1 at pH 6 and above at any experimental temperature went in different way than in acidic environment and resulted in a complex mixture of degradants.…”

Section: Resultsmentioning

confidence: 99%

Crystal Structure and Physicochemical Properties of Crystalline Form of 2′-O-{3-[(7-chloro-4-quinolinyl)amino]propyl}-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A

Filić

Starčević

Pešić

et al. 2011

Journal of Pharmaceutical Sciences

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“…In a first attempt to prepare a ketolide from protected erythromycin 9-oxime [115], a hemiketal was formed. After oxidation of its 3-decladinosyl derivative, the free 6-hydroxy group reacted with the 3-oxo group.…”

Section: Hemiketals Spiroketals and Iminoethersmentioning

confidence: 99%

Azalides from Azithromycin to New Azalide Derivatives

Mutak

2007

J Antibiot

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Azalides are semi-synthetic macrolides, in which a nitrogen atom is introduced into a macrolactone ring via a Beckmann rearrangement. Starting from erythromycin, oximes, depending on the reaction conditions lactams, or bicyclic-imino-ethers were formed, which were further reduced to aminolactones. The cyclic amine 9a-became the precursor for novel, significantly more active derivatives, especially for 9-dihydro-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A with the generic name azithromycin. It showed a broad spectrum of antibacterial activity covering all significant bacteria causing respiratory tract infections. The greatest advantages of azithromycin are its unusual pharmacokinetics (high tissue distribution), metabolic stability and high tolerability. These properties have led in recent years to the widespread use of the azalide scaffold for the synthesis of new compounds with advantageous pharmacokinetics.The azalide scaffold possesses an amino and several hydroxyl groups, which could be substituted or transformed to obtain new compounds. Different derivatives were obtained by substitution on the nitrogen but a large variety of derivatives, such as ethers, esters and carbamates, were made by reactions with various hydroxyl groups. Substitutions on both nitrogen and hydroxyl or two hydroxyl groups yielded new, bridged compounds. The 4Љ-hydroxy group was oxidized to 4-oxo-, which was transformed via the oxime to 4-amino, or via epoxide to 4Љ-methylamino compounds. Cleavage of the cladinose sugar and further transformations gave 3-acyl or 3-oxo compounds, which were less active than 14-membered acylides or ketolides. Beckmann rearrangement of some 16-membered macrolide oximes yielded only 17-membered lactams, which were less active than starting macrolides, and could not be reduced to amines.Intramolecular rearrangement of azalide imino-ethers yielded 13-membered azalides. Some new 11a-azalides were obtained after oxidative cleavage of some 16-membered macrolides and additional cyclisation.

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Glycoside cleavage reactions on erythromycin A. Preparation of erythronolide A

Cited by 56 publications

References 5 publications

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

Crystal Structure and Physicochemical Properties of Crystalline Form of 2′-O-{3-[(7-chloro-4-quinolinyl)amino]propyl}-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A

Azalides from Azithromycin to New Azalide Derivatives

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