Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities

Chandrika, Nishad Thamban; Garneau‐Tsodikova, Sylvie

doi:10.1039/c7cs00407a

Cited by 58 publications

(55 citation statements)

References 323 publications

(263 reference statements)

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“…Various reviews have previously described both aminoglycoside modification and their conjugation to other chemical moieties. [17] Herein, we present an update of current methodologies used for the specific conjugation of aminoglycosides to other chemical moieties, focusingo nt he rationalef or the addition of such modifications andonhow these modifications influencet he affinity and specificity for the considered RNA target. We chose to classify these chemicalc onjugations according to the moieties attached to aminoglycosides to clearly illustrate why these moieties were chosen to improve affinity,s electivity, biological activity,a nd therapeutic applicationsa nd how they were chemically linked to aminoglycosides.…”

Section: Introductionmentioning

confidence: 99%

Aminoglycoside Conjugation for RNA Targeting: Antimicrobials and Beyond

Aradi

Giorgio

Duca

2020

Chemistry A European J

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Natural aminoglycosides are therapeutically useful antibiotics and very efficient RNA ligands. They are oligosaccharides that contain several ammonium groups able to interfere with the translation process in prokaryotesu pon binding to bacterial ribosomal RNA (rRNA), and thus, impairing protein synthesis. Even if aminoglycosides are commonly used in therapy,t hese RNA bindersl ack selectivity and are able to bind to aw ide number of RNA sequences/structures. This is one of the reasons for their toxicitya nd limited applications in therapy.A tt he same time, the ability of aminoglycosides to bind to various RNAs renders them ag reat source of inspirationf or the synthesis of new bindersw ith improved affinity and specificity toward several therapeutically relevant RNA targets. Thus, an umber of studies have been performed on these complex and highly functionalized compounds, leading to the development of various synthetic methodologies toward the synthesis of conjugated aminoglycosides. The aim of this review is to highlight recent progress in the field of aminoglycoside conjugation,p aying particulara ttention to modificationsp erformed toward the improvement of affinity and especiallyt ot he selectivity of the resulting compounds. This will help readers to understand how to introduce ad esired chemical modification for future developments of RNA ligandsa sa ntibiotics, antiviral, and anticancer compounds.

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Section: Introductionmentioning

confidence: 99%

Aminoglycoside Conjugation for RNA Targeting: Antimicrobials and Beyond

Aradi

Giorgio

Duca

2020

Chemistry A European J

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“…Aminoglycosides (AGs), for example, neomycin B (NEO) 1 , paromomycin (PARO) 2 , kanamycins A and B (KANA, KANB) 3 , 4 and tobramycin 5 ( Figure 1 ), constitute a large family of highly potent broad-spectrum antibiotic drugs. These naturally occurring hydrophilic pseudo-oligosaccharides, which are polycationic species at physiological pH, target ribosomal RNA and disrupt protein synthesis [ 1 ]. Unfortunately, the widespread clinical use of AGs has strongly reduced their clinical efficacy through the selection of resistant bacteria [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Amphiphilic Aminoglycosides as Medicinal Agents

Dezanet

Kempf

Mingeot‐Leclercq

et al. 2020

IJMS

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The conjugation of hydrophobic group(s) to the polycationic hydrophilic core of the antibiotic drugs aminoglycosides (AGs), targeting ribosomal RNA, has led to the development of amphiphilic aminoglycosides (AAGs). These drugs exhibit numerous biological effects, including good antibacterial effects against susceptible and multidrug-resistant bacteria due to the targeting of bacterial membranes. In the first part of this review, we summarize our work in identifying and developing broad-spectrum antibacterial AAGs that constitute a new class of antibiotic agents acting on bacterial membranes. The target-shift strongly improves antibiotic activity against bacterial strains that are resistant to the parent AG drugs and to antibiotic drugs of other classes, and renders the emergence of resistant Pseudomonas aeruginosa strains highly difficult. Structure–activity and structure–eukaryotic cytotoxicity relationships, specificity and barriers that need to be crossed in their development as antibacterial agents are delineated, with a focus on their targets in membranes, lipopolysaccharides (LPS) and cardiolipin (CL), and the corresponding mode of action against Gram-negative bacteria. At the end of the first part, we summarize the other recent advances in the field of antibacterial AAGs, mainly published since 2016, with an emphasis on the emerging AAGs which are made of an AG core conjugated to an adjuvant or an antibiotic drug of another class (antibiotic hybrids). In the second part, we briefly illustrate other biological and biochemical effects of AAGs, i.e., their antifungal activity, their use as delivery vehicles of nucleic acids, of short peptide (polyamide) nucleic acids (PNAs) and of drugs, as well as their ability to cleave DNA at abasic sites and to inhibit the functioning of connexin hemichannels. Finally, we discuss some aspects of structure–activity relationships in order to explain and improve the target selectivity of AAGs.

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“…The effectiveness of this approach has been illustrated by the synthesis of derivatives of vancomycin, a potent inhibitor of bacterial cell wall synthesis, that overcome vancomycin-resistant enterococci infections [1]. Major efforts have been directed towards the (semi) synthesis of analogues of carbohydrate-based antibiotics, and in particular aminoglycosides [2,3]. Aminoglycosides are natural products that are highly cationic in nature and show bactericidal activity, as they bind the 30S component of the bacterial ribosome, thereby blocking protein synthesis and inhibiting bacterial growth [4].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, there are multiple enzymes that work on aminoglycosides to inactivate their antibiotic activity, which limits their use in the clinic [5]. A large variety of structural analogues, including amphiphilic aminoglycosides [6], conformationally-locked aminoglycosides, and glycosylated aminoglycosides [7,8] have been synthesized to overcome the adverse effects [3]. These efforts led to the discovery of derivatives that cannot be modified by aminoglycoside-inactivating enzymes [9,10], that have reduced toxicity [6], and even inhibit bacterial growth via new mechanisms of action [11,12].…”

Section: Introductionmentioning

confidence: 99%

Selective Modification of Streptozotocin at the C3 Position to Improve Its Bioactivity as Antibiotic and Reduce Its Cytotoxicity towards Insulin-Producing β Cells

et al. 2020

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With the increasing resistance of bacteria to current antibiotics, novel compounds are urgently needed to treat bacterial infections. Streptozotocin (STZ) is a natural product that has broad-spectrum antibiotic activity, albeit with limited use because of its toxicity to pancreatic β cells.In an attempt to derivatize STZ through structural modification at the C3 position, we performed the synthesis of three novel STZ analogues by making use of our recently developed regioselective oxidation protocol. Keto-STZ (2) shows the highest inhibition of bacterial growth (minimum inhibitory concentration (MIC) and viability assays), but is also the most cytotoxic compound. Pre-sensitizing the bacteria with GlcNAc increased the antimicrobial effect, but did not result in complete killing. Interestingly, allo-STZ (3) revealed moderate concentration-dependent antimicrobial activity and no cytotoxicity towards β cells, and deoxy-STZ (4) showed no activity at all.

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Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities

Cited by 58 publications

References 323 publications

Aminoglycoside Conjugation for RNA Targeting: Antimicrobials and Beyond

Aminoglycoside Conjugation for RNA Targeting: Antimicrobials and Beyond

Amphiphilic Aminoglycosides as Medicinal Agents

Selective Modification of Streptozotocin at the C3 Position to Improve Its Bioactivity as Antibiotic and Reduce Its Cytotoxicity towards Insulin-Producing β Cells

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