A Concise Synthesis of Carolacton

Hallside, Michal S.; Brzozowski, Richard S.; Wuest, William M.; Phillips, Andrew J.

doi:10.1021/ol500004k

Cited by 31 publications

(39 citation statements)

References 36 publications

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“…290 To construct macrocycle precursor 400 , gulonolactone derivative 397 was oxidized and olefinated to 398 , and hydrolysis followed by Swern oxidation furnished lactone 399 . A vinylogous (S N 2′) substitution with a diallylcuprate provided acid 400 as a single diastereomer.…”

Section: Narrow-spectrum Small Molecule Natural Productsmentioning

confidence: 99%

Natural Products as Platforms To Overcome Antibiotic Resistance

2017

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Natural products have served as powerful therapeutics against pathogenic bacteria since the golden age of antibiotics of the mid-20th century. However, the increasing frequency of antibiotic-resistant infections clearly demonstrates that new antibiotics are critical for modern medicine. Because combinatorial approaches have not yielded effective drugs, we propose that the development of new antibiotics around proven natural scaffolds is the best short-term solution to the rising crisis of antibiotic resistance. We analyze herein synthetic approaches aiming to reengineer natural products into potent antibiotics. Furthermore, we discuss approaches in modulating quorum sensing and biofilm formation as a nonlethal method, as well as narrowspectrum pathogen-specific antibiotics, which are of interest given new insights into the implications of disrupting the microbiome.

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Section: Narrow-spectrum Small Molecule Natural Productsmentioning

confidence: 99%

Natural Products as Platforms To Overcome Antibiotic Resistance

2017

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“…Only recently, a second total synthesis and the preparation of derivatives were disclosed by the group of Phillips. 24 Both studies paved the way for the preparation of analogues. In this report, we disclose a detailed study of the inhibitory effect of carolacton 1 and several carolacton derivatives 2-7 on biofilms comprised of the oral species S. mutans, S. gordonii, S. oralis or A. actinomycetemcomitans.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of new carolacton derivatives and their activity against biofilms of oral bacteria

et al. 2015

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Carolacton, a secondary metabolite isolated from the extracts of Sorangium cellulosum, causes membrane damage and cell death in biofilms of the caries-and endocarditis-associated bacterium Streptococcus mutans. Here, we report the total synthesis of several derivatives of carolacton. All new structural modifications introduced abolished its biological activity, including subtle ones, such as inversion of configuration at C9. However, a bicyclic bislactone derivative as well as the methyl ester of carolacton resulted in compounds with prodrug properties. Their inhibitory activity on S. mutans was proven to be based on enzymatic hydrolysis by S. mutans which provided native carolacton resulting in biofilm damage in vivo. Moreover, we demonstrate that carolacton acts also on S. gordonii, S. oralis and the periodontitis pathogen Aggregatibacter actinomycetemcomitans, causing elongated cells and growth inhibition.

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“…Chemical genetic investigations as to the mechanism by which carolacton elicits its effect have yet to be reported. Additionally, the total synthesis from Kirschning and Phillips (discussed below) resulted in the production of analogs, which, upon biological testing, were shown to possess effects similar to that of carolacton, albeit at lower concentration. This result highlights the idea that small changes to the structure of such compounds can result in drastic differences in biological activity, warranting future investigation into analog library synthesis, as such interrogation may provide SAR clues and inform the MoA.…”

Section: Other Examples Of 12‐membered Macrolactonesmentioning

confidence: 99%

“…Additionally, in 2014, our group in collaboration with Phillips and Hallside reported a total synthesis (Scheme B) that significantly improved on previous efforts . Starting from the Evans beta‐ketoimide, the sidechain 121 was made as a single diastereomer and relied on a Leighton crotylation to introduce the functionality required for both esterification and RCM.…”

Section: Other Examples Of 12‐membered Macrolactonesmentioning

confidence: 99%

Twelve‐membered macrolactones: privileged scaffolds for the development of new therapeutics

Brzozowski

Wuest

2017

Chem Biol Drug Des

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Natural products commonly produced as secondary metabolites of various plants and micro-organisms represent a diverse chemical space of compounds. The diversity of natural products makes them an attractive target for interrogation by both chemists and biologists alike. Indeed, the study of 12-membered macrolactones has already led to the discovery of lead drug compounds and new biological targets, which has motivated the development of diverted total synthetic routes to libraries of analogs. This review explores the discovery, biological characterization, and synthesis of several 12-membered macrolactones, exploiting examples that underscore their importance in the drug discovery field. It is our hope that this review will motivate further interest in this class of natural products, a group of molecules that we think merit the classification of 'privileged scaffolds' within the medicinal chemistry community, to further investigate and develop novel compounds with promising bioactivity. K E Y W O R D Santibiotic, biosynthesis, diverted total synthesis, macrolactone, natural product

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A Concise Synthesis of Carolacton

Cited by 31 publications

References 36 publications

Natural Products as Platforms To Overcome Antibiotic Resistance

Natural Products as Platforms To Overcome Antibiotic Resistance

Synthesis of new carolacton derivatives and their activity against biofilms of oral bacteria

Twelve‐membered macrolactones: privileged scaffolds for the development of new therapeutics

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