Siderophore–fluoroquinolone conjugates containing potential reduction-triggered linkers for drug release: synthesis and antibacterial activity

Ji, Cheng; Miller, Marvin J.

doi:10.1007/s10534-015-9830-3

Cited by 45 publications

(58 citation statements)

References 33 publications

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“…Complete release of the ciprofloxacin from the conjugate 31j was achieved after 25 min under mild conditions (37 °C, 20-fold excess of sodium dithionite). Antibacterial activity assays indicated that drug release occurred inside the bacterial cells; however, the conjugates 31j , 31k were less active relative to the parent drug [92] (Fig. 9).…”

Section: Siderophoresmentioning

confidence: 99%

Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules

Fedorowicz

Sączewski

2018

Monatsh Chem

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This review is aimed to provide extensive survey of quinolones and fluoroquinolones for a variety of applications ranging from metal complexes and nanoparticle development to hybrid conjugates with therapeutic uses. The review covers the literature from the past 10 years with emphasis placed on new applications and mechanisms of pharmacological action of quinolone derivatives. The following are considered: metal complexes, nanoparticles and nanodrugs, polymers, proteins and peptides, NO donors and analogs, anionic compounds, siderophores, phosphonates, and prodrugs with enhanced lipophilicity, phototherapeutics, fluorescent compounds, triazoles, hybrid drugs, bis-quinolones, and other modifications. This review provides a comprehensive resource, summarizing a broad range of important quinolone applications with great utility as a resource concerning both chemical modifications and also novel hybrid bifunctional therapeutic agents.Graphical abstract

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Section: Siderophoresmentioning

confidence: 99%

Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules

Fedorowicz

Sączewski

2018

Monatsh Chem

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“…[33] For severala ntimicrobial drugs addressing ac omplex biological target in the cytosol of bacteria, such as fluoroquinolones inhibiting the DNA gyrase, it has been demonstrated that appropriate cleavable linkers between the siderophore and the drug are required to allow releasea nd proper binding to the drug target. [31,37] Wang and co-workersh ave recently reported an approach to esterase-sensitive TML-based prodrugs of hydrogen sulfide (Scheme 7). [31,37] Wang and co-workersh ave recently reported an approach to esterase-sensitive TML-based prodrugs of hydrogen sulfide (Scheme 7).…”

Section: Different Triggers For Trimethyl Lockmentioning

confidence: 99%

“…[37,123] They reported desferrioxamin B-ciprofloxacin conjugates 85 as well as agrobactin-derived synthetic siderophore-ciprofloxacin conjugate 86,b earing both quinone-based and urea-substituted TML cores as oxidoreductase sensitive linkers (Scheme 17). [37,123] They reported desferrioxamin B-ciprofloxacin conjugates 85 as well as agrobactin-derived synthetic siderophore-ciprofloxacin conjugate 86,b earing both quinone-based and urea-substituted TML cores as oxidoreductase sensitive linkers (Scheme 17).…”

Section: Quinone-oxidoreductase-sensitive Tml Systemsmentioning

confidence: 99%

“…[34][35][36] In their report, Miller and Ji link the Nterminus of ciprofloxacin 22 (Scheme 6) through an amide bond to the carboxylic acid of aT ML core and attach desferrioxamin B( 23), as iderophore and xenosiderophore of several Gram-positive and Gram-negative bacteria, through as hort succinyl spacer to the phenolic hydroxy group of aT ML moiety.R esulting desferrioxaminciprofloxacin conjugate 21 shows increased growth inhibitory activity against the Gram-negative pathogen Pseudomonasa er-uginosa in an agar diffusion assay compared to the parent ciprofloxacin and noncleavablea nalogue 24. [31,37] Wang and co-workersh ave recently reported an approach to esterase-sensitive TML-based prodrugs of hydrogen sulfide (Scheme 7). [38] Hydrogen sulfide is an endogenously produced important signaling molecule in the cardiovascular and nervous systems of mammals and plays akey role in the pathogenesis of several diseases.…”

Section: Esterase-sensitive Tmls Ystemsmentioning

confidence: 99%

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Trimethyl Lock: A Multifunctional Molecular Tool for Drug Delivery, Cellular Imaging, and Stimuli‐Responsive Materials

Okoh

Klahn

2018

ChemBioChem

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Trimethyl lock (TML) systems are based on ortho-hydroxydihydrocinnamic acid derivatives displaying increased lactonization reactivity owing to unfavorable steric interactions of three pendant methyl groups, and this leads to the formation of hydrocoumarins. Protection of the phenolic hydroxy function or masking of the reactivity as benzoquinone derivatives prevents lactonization and provides a trigger for controlled release of molecules attached to the carboxylic acid function through amides, esters, or thioesters. Their easy synthesis and possible chemical adaption to several different triggers make TML a highly versatile module for the development of drug-delivery systems, prodrug approaches, cell-imaging tools, molecular tools for supramolecular chemistry, as well as smart stimuliresponsive materials.

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“…4,5 The chemical nature of the trimethyl lock is an o-hydroxylcinnamic acid derivative. 6 Reduction of the quinone trimethyl lock system generalized by structure 1 would lead to the corresponding hydroquinones 2 in which severe steric repulsion between three methyl groups promotes rapid lactonization with concomitant release of an alcohol or amine (Scheme 1).…”

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confidence: 99%

Syntheses and Antibacterial Activity of N-Acylated Ciprofloxacin Derivatives Based on the Trimethyl Lock

Miller

2015

ACS Med. Chem. Lett.

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Several N-acyl ciprofloxacin quinone derivatives based on a trimethyl lock structure were synthesized, and their in vitro antibacterial activity against a panel of clinically relevant bacteria was evaluated. A few new analogues displayed enhanced activity against Gram-positive species compared to the parent drug. Additionally, studies of 8-Cip, which was the most potent compound tested, indicate that it may act through a dual-action mechanism.KEYWORDS: Ciprofloxacin, trimethyl lock, drug release, antibacterial S ince their discovery in 1970s, fluoroquinolone antibiotics have played an important role in treatment of bacterial infections and have saved countless millions of lives. Targeting bacterial DNA gyrase and topoisomerase, fluoroquinolones exhibit their significant bactericidal activity by forming ternary complexes of enzyme−DNA−drug and consequently blocking bacterial replication. 1,2 Their notable antimicrobial activity, excellent pharmacokinetic properties, and few side effects have led to the widespread use of fluoroquinolones and, unfortunately, thus also the development of bacterial resistance. 3 Therefore, although many advances in the search for new fluoroquinolones have been already made, there is a sense of urgency for new and more effective derivatives.Recently, in our development of linkers to incorporate a drug release function in iron transport-mediated drug delivery, a series of carboxylic acids with a quinone "trimethyl lock" structure and their methyl esters were obtained as synthetic intermediates. 4,5 The chemical nature of the trimethyl lock is an o-hydroxylcinnamic acid derivative. 6 Reduction of the quinone trimethyl lock system generalized by structure 1 would lead to the corresponding hydroquinones 2 in which severe steric repulsion between three methyl groups promotes rapid lactonization with concomitant release of an alcohol or amine (Scheme 1). 7,8 Several quinone trimethyl lock compounds have been investigated for reductase-activated prodrugs such as those based on mustard 9 and oxindoles 10 for anticancer therapy. In ciprofloxacin, one of the best known fluoroquinolones, it has been demonstrated that chemical modification of the secondary amine in the piperazinyl ring by acylation does not always alter the effect of these molecules toward their bacterial target. 11 With the aim of probing the effects of the quinone trimethyl lock on antibacterial activity of fluoroquinonlones, we herein describe the syntheses of several ciprofloxacin derivatives with quinone trimethyl lock precursors as N-acyl substituents and studies of their in vitro antibacterial activity.The syntheses of trimethyl locks with different substituents on the quinone are shown in Scheme 2. Both forms 5H and 8H were derived from lactone 4 by oxidative ring opening of the

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Siderophore–fluoroquinolone conjugates containing potential reduction-triggered linkers for drug release: synthesis and antibacterial activity

Cited by 45 publications

References 33 publications

Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules

Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules

Trimethyl Lock: A Multifunctional Molecular Tool for Drug Delivery, Cellular Imaging, and Stimuli‐Responsive Materials

Syntheses and Antibacterial Activity of N-Acylated Ciprofloxacin Derivatives Based on the Trimethyl Lock

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