Conversion of leucomycin-A3 antibiotic into novel triazole analogues via regio- and diastereoselective SN1′ substitution with allylic rearrangement and 1,3-dipolar cycloaddition of CuAAC type

Domagalska, Joanna; Pyta, Krystian; Przybylski, Piotr

doi:10.1016/j.tetlet.2016.02.113

Cited by 4 publications

(5 citation statements)

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“…Introduction of substituents of increasing size at the C13 position of aglycone was motivated by previously reported docking models that showed a gap between the bonded 16‐membered lactone macrolide and the L37E and L4 protein subunits of ribosomes. Recently, we described a synthetic strategy that enables the introduction of structurally diverse substituents at the C13 position of josamycin′s aglycone in a regioselective manner . Using the approach with S N 1’ allylic rearrangement and dipolar Huisgen cycloaddition, we expanded the series of α,β‐unsaturated josamycin analogues by new ether (compounds 4 – 9 ) and new triazole entities (compounds 13 , 14 , and 18 – 23 ) (Scheme ).…”

Section: Methodsmentioning

confidence: 99%

“…Recently,w ed escribed as ynthetic strategy that enables the introduction of structurally diverses ubstituents at the C13 position of josamycin'sa glycone in ar egioselective manner. [16] Using the approach with S N 1' allylic rearrangement and dipolar Huisgenc ycloaddition,w ee xpanded the series of a,b-unsaturated josamycin analogues by new ether (compounds 4-9)a nd new triazole entities (compounds 13, 14,a nd 18-23)( Scheme1). All josamycind erivatives were characterized in detail by HPLC, ESIMS, 1D and 2D NMR, as wella sF TIR spectroscopy (Supporting Information).…”

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confidence: 99%

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16‐Membered Macrolide Lactone Derivatives Bearing a Triazole‐Functionalized Arm at the Aglycone C13 Position as Antibacterial and Anticancer Agents

et al. 2016

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A series of new C13-triazole-bridged and C13-ether leucomycin analogues with a reduced aldehyde group were synthesized. Derivatives with the highest antibacterial [MIC values (S. epidermidis, S. pneumoniae): ∼2-4 μg mL(-1) ; 2.55-5.09 μm] and cytotoxic [IC50 values (HeLa, KB, MCF-7, A549, HepG2 cells): ∼1.35-3.70 μm] potencies were those with the best aqueous solubility and bearing a saccharide-triazole arm at the C13 position of the aglycone. These derivatives preferentially bind at the ribosomal tunnel and show the most attractive selectivity indexes [SI; calculated relative to the human dermal fibroblast (HDF) cell line], even higher than that of the reference compound cytarabine. Results of molecular docking studies of this type of macrolide antibiotics at the ribosomal tunnel, together with experimentally determined lipophilicity and aqueous solubility values, as well as biological assay data revealed the importance of the introduced functional group at the aglycone C13 arm to the future design of anticancer and antibacterial drug candidates. Our results clearly indicate that the high antibacterial and anticancer activities of these types of macrolides do not necessarily depend on the presence of the aldehyde group at the aglycone lactone ring.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

16‐Membered Macrolide Lactone Derivatives Bearing a Triazole‐Functionalized Arm at the Aglycone C13 Position as Antibacterial and Anticancer Agents

et al. 2016

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“…The bulkiness of the alkoxy and acyloxy substituents further lower the reactivity of saccharide-derived electrophiles towards SN2 reactions [154]. Especially, the higher stability of the chair conformation of the six-membered saccharide ring and the presence of multiple equatorial substituents makes it difficult for the completion of an SN2 attack the secondary position of the target saccharide [155]. Mechanistically, the formation of SN2 transition state involves changes in the ring conformation for accommodating the attacking nucleophile, and the leaving group around the central carbon.…”

Section: Chemical Modificationsmentioning

confidence: 99%

Current-status and applications of polysaccharides in drug delivery systems

Prasher

Sharma

Mehta

et al. 2021

Colloid and Interface Science Communications

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The polysaccharide-based advanced drug delivery system owing to their biocompatibility, ability to encapsulate the drug molecules in their interspaces, and ability to achieve a controlled release of the cargo drug molecules result in improved drug pharmacokinetics. The drug-loaded polysaccharides possess ability to evade the multidrug-resistant microbial efflux pumps by aggregation effect, whereas the drug loaded polysaccharidefabricated metal nanoparticles present an exceptional candidature for effectively transporting the drug molecules across the membrane barriers while enabling the theranostic applications at the same time. The biodegradability of polysaccharide based drug delivery systems ensure a sustained release of the encapsulated drug molecules, which minimizes the side effects caused by a burst release of the cargo therapeutics. These drug delivery systems proved highly beneficial for the NSAIDs that otherwise manifest ulcerogenic effect in the gastrointestinal tract. The large surface area of polysaccharides further provide a higher drug-loading capacity, which maintains the optimal concentration of the cargo drug at the target sites. The emerging applications of biodegradable polysaccharides in the designing of multicompartmental microspheres revolutionized tissue engineering, multi drug delivery, and cell culturing technologies. The present review deals with the current-status of polysaccharides as advanced drug delivery systems.

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“…Many 16‐membered macrolides and their derivatives have relatively good gastric tolerance and low tendency to produce allergy and induce resistance . Josamycin and its derivatives are typical examples . Josamycin (leucomycin A 3 ), produced by fermentation of Streptomyces narbonensis var.…”

Section: Introductionmentioning

confidence: 99%

“…1 Josamycin and its derivatives are typical examples. [2][3][4][5][6] Josamycin (leucomycin A 3 ), produced by fermentation of Streptomyces narbonensis var. Josamyceticus, 7 consists of a 16membered ring aglycone and a disaccharide (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a new component and impurities in josamycin by trap‐free two‐dimensional liquid chromatography coupled to ion trap time‐of‐flight mass spectrometry

Liu

Sang

et al. 2019

Rapid Comm Mass Spectrometry

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Rationale The toxicities of the impurities of a drug will affect the clinical effects and cause potential health risk; therefore, it is essential to study profiles of the impurities. In this study, a new structural type of component and two acid degradation impurities in josamycin were discovered and characterized for the further improvement of official monographs in pharmacopoeias. Methods The component and acid degradation impurities in josamycin were separated and preliminary characterized by trap‐free two‐dimensional liquid chromatography coupled to high‐resolution ion trap time‐of‐flight mass spectrometry (2D LC/IT‐TOF MS) in both positive and negative electrospray ionization mode. The eluent of each peak from the first dimensional chromatographic system was trapped by a switching valve and subsequently transferred to the second dimensional chromatographic system, which was connected to the mass spectrometer. Full scan MS was firstly conducted to obtain the exact m/z values of the molecules. Then LC/MS/MS and LC/MS/MS/MS experiments were performed on the compounds of interest. Results A new structural type of component, which was named as josamycin A, and two acid degradation impuritiess, which were identified as impurity I and impurity II, were discovered in josamycin. Their structures and fragmentation pattern were deduced according to MSn data. Furthermore, josamycin A was synthesized and impurity I was separated by preparative HPLC. The structures of josamycin A and the impurities were confirmed by 1H NMR and 13C NMR data. Conclusions Josamycin A was produced when the hydroxyl group on the macrolide of josamycin was oxidized into a carbonyl group. Impurity I and impurity II were produced by the loss of one molecule of acetyl mycaminose from josamycin and josamycin A, respectively. Compared with josamycin, the experimental results showed that josamycin A had a higher antibacterial activity with similar cytotoxicity, while impurity I had no antibacterial activity but a higher cytotoxicity. As a result, the control of impurity I is significant.

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Conversion of leucomycin-A3 antibiotic into novel triazole analogues via regio- and diastereoselective SN1′ substitution with allylic rearrangement and 1,3-dipolar cycloaddition of CuAAC type

Cited by 4 publications

References 54 publications

16‐Membered Macrolide Lactone Derivatives Bearing a Triazole‐Functionalized Arm at the Aglycone C13 Position as Antibacterial and Anticancer Agents

16‐Membered Macrolide Lactone Derivatives Bearing a Triazole‐Functionalized Arm at the Aglycone C13 Position as Antibacterial and Anticancer Agents

Current-status and applications of polysaccharides in drug delivery systems

Characterization of a new component and impurities in josamycin by trap‐free two‐dimensional liquid chromatography coupled to ion trap time‐of‐flight mass spectrometry

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