Synthesis and biological activity of new 5-O-sugar modified ketolide and 2-fluoro-ketolide antibiotics

Liang, Chang-Hsing; Yao, Sulan; Chiu, Yu-Hung; Leung, Po Yee; Robert, Nicole; Seddon, Jaime; Sears, P.S.; Hwang, Cheol Kyu; Ichikawa, Yoshi; Romero, Alex

doi:10.1016/j.bmcl.2005.01.027

Cited by 39 publications

(18 citation statements)

References 9 publications

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“…Other structure modifications included the following: modified 5‐ O ‐desosamine ketolides (Chen et al ., ), fluorination at the C2‐ and/or C12 positions (Denis and Bonnefoy, ; Krokidis et al ., ), variation of the cyclic carbonate and hydrazono‐carbamate at 11,12 positions (Hunziker et al ., ; Andreotti et al ., ; Zhu et al ., ) or variation of the aglycon ring (Shaw et al ., ; Ashley et al ., ; Sugimoto and Tanikawa, ). Lastly, modifications also included replacement of desosamine with different sugars (Liang et al ., ; Romero et al ., ; Chen et al ., ). A detailed review covering all the chemical efforts to improve the ketolide activity is presented in the review of Liang and Han ().…”

Section: Antimicrobial Activity and Chemical Derivatizationmentioning

confidence: 98%

The macrolide antibiotic renaissance

Dinos

2017

British J Pharmacology

326

221

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Macrolides represent a large family of protein synthesis inhibitors of great clinical interest due to their applicability to human medicine. Macrolides are composed of a macrocyclic lactone of different ring sizes, to which one or more deoxy-sugar or amino sugar residues are attached. Macrolides act as antibiotics by binding to bacterial 50S ribosomal subunit and interfering with protein synthesis. The high affinity of macrolides for bacterial ribosomes, together with the highly conserved structure of ribosomes across virtually all of the bacterial species, is consistent with their broad-spectrum activity. Since the discovery of the progenitor macrolide, erythromycin, in 1950, many derivatives have been synthesised, leading to compounds with better bioavailability and acid stability and improved pharmacokinetics. These efforts led to the second generation of macrolides, including well-known members such as azithromycin and clarithromycin. Subsequently, in order to address increasing antibiotic resistance, a third generation of macrolides displaying improved activity against many macrolide resistant strains was developed. However, these improvements were accompanied with serious side effects, leading to disappointment and causing many researchers to stop working on macrolide derivatives, assuming that this procedure had reached the end. In contrast, a recent published breakthrough introduced a new chemical platform for synthesis and discovery of a wide range of diverse macrolide antibiotics. This chemical synthesis revolution, in combination with reduction in the side effects, namely, 'Ketek effects', has led to a macrolide renaissance, increasing the hope for novel and safe therapeutic agents to combat serious human infectious diseases.

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Section: Antimicrobial Activity and Chemical Derivatizationmentioning

confidence: 98%

The macrolide antibiotic renaissance

Dinos

2017

British J Pharmacology

326

221

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“…38 Escherichia coli 70S ribosomes, 50S and 30S ribosomal subunits were isolated as described. 39 After optimizing the concentrations of ribosomes, azide 2 , and commercial 3-ethynylaniline ( 3 ) in tris(hydroxymethyl)-aminomethane (Tris) buffer, we found that 5 [.proportional]M 70S ribosomes or 50S subunits, 5 μM azide, and 5 mM alkyne at rt for 24–48 h resulted in the formation of 1 and its syn (1,5)-regioisomer (~2:1 ratio) in 12 ± 4-fold greater amounts than in the absence of 70S ribosome or 50S subunit (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

Ribosome-Templated Azide–Alkyne Cycloadditions: Synthesis of Potent Macrolide Antibiotics by In Situ Click Chemistry

et al. 2016

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Over half of all antibiotics target the bacterial ribosome-Nature's complex, 2.5 MDa nanomachine responsible for decoding mRNA and synthesizing proteins. Macrolide antibiotics, exemplified by erythromycin, bind the 50S subunit with nM affinity and inhibit protein synthesis by blocking the passage of nascent oligopeptides. Solithromycin (1), a third-generation semisynthetic macrolide discovered by combinatorial copper-catalyzed click chemistry, was synthesized in situ by incubating either E. coli 70S ribosomes or 50S subunits with macrolidefunctionalized azide 2 and 3-ethynylaniline (3) precursors. The ribosome-templated in situ click method was expanded from a binary reaction (i.e., one azide and one alkyne) to a sixcomponent reaction (i.e., azide 2 and five alkynes) and ultimately to a sixteen-component reaction (i.e., azide 2 and fifteen alkynes). The extent of triazole formation correlated with ribosome affinity for the anti (1,4)-regioisomers as revealed by measured K d values. Computational analysis using the Site-Identification by Ligand Competitive Saturation (SILCS) approach indicated that the relative affinity of the ligands was associated with the alteration of macrolactone+desosamine- HHS Public Access

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“…These compounds are promising agents for the treatment of respiratory pathogens resistant to erythromycin A (Fig. 20) [37,38].…”

Section: Erythromycinmentioning

confidence: 99%

Recent advances (1995–2005) in fluorinated pharmaceuticals based on natural products

Bégué¹,

Bonnet‐Delpon²

2006

Journal of Fluorine Chemistry

568

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Synthesis and biological activity of new 5-O-sugar modified ketolide and 2-fluoro-ketolide antibiotics

Cited by 39 publications

References 9 publications

The macrolide antibiotic renaissance

The macrolide antibiotic renaissance

Ribosome-Templated Azide–Alkyne Cycloadditions: Synthesis of Potent Macrolide Antibiotics by In Situ Click Chemistry

Recent advances (1995–2005) in fluorinated pharmaceuticals based on natural products

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