A Unified Synthetic Approach to Optically Pure Curvularin-Type Metabolites

Allu, Srinivasa Rao; Banne, Sreenivas; Jiang, Jiahuan; Qi, Na; Guo, Jingjie; He, Yun

doi:10.1021/acs.joc.9b00776

Cited by 17 publications

(6 citation statements)

References 41 publications

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“…Additionally, the extracts inhibited pyocyanin production by a lasR mutant of the PA14 strain, and this inhibition was reversed when cultures were supplemented with exogenous BHL, but not with OdDHL or PQS (data not shown), suggesting that RhlR was selectively inhibited by factors in the extract fraction ( Kim et al 2019 ). Thus, an active compound was isolated from the culture extracts of the fungal strain via bioassay-guided fractionation and then identified as (−)-curvularin by mass and NMR spectral analysis; in addition, a specific rotation value ([α] D , −23.8, c 0.1, MeOH) was obtained, and it was almost the same as the value ([α] D , −23.4, c 0.1, MeOH) reported in the literature ( Allu et al, 2019 ; Supplementary Figures 1 , 2 ; Supplementary Table 2 ). The purity of isolated curvularin was determined to be 98.3% at 220 nm by analytical HPLC ( Supplementary Figure 3 ).…”

Section: Resultssupporting

confidence: 71%

Curvularin Isolated From Phoma macrostoma Is an Antagonist of RhlR Quorum Sensing in Pseudomonas aeruginosa

Choi

Kim

2022

Front. Microbiol.

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Quorum sensing (QS) is an attractive target for the treatment of multidrug-resistant Pseudomonas aeruginosa, against which new antibiotics are urgently needed. Because LasR is at the top of the QS hierarchy controlling Rhl and PQS systems, most QS inhibitors have been targeted to LasR. However, it has recently been reported that in clinical isolates of P. aeruginosa, LasR is frequently mutated and nonfunctional, and RhlR independently acts to produce virulent factors that maintain toxicity. Thus, for effective treatment of chronic cystic fibrosis infections, RhlR antagonists is needed to prevent the LasR-independent Rhl system, but RhlR antagonists have rarely been reported. In this study, we found that curvularin, an aromatic compound with a cyclized alkyl side chain isolated from Phoma macrostoma, at a low micromolar concentration of 1–30 μM potently and selectively inhibited pyocyanin and rhamnolipid production without affecting the cell viability of P. aeruginosa. Only high concentration (more over 100 μM) curvularin negligibly inhibited biofilm formation and elastase production, suggesting that curvularin at low concentrations selectively inhibits RhlR. The QS antagonism by curvularin was investigated in experiments using QS competition and signaling molecules assays with QS gene expression analysis, and the results showed that, indeed, at low concentrations, curvularin selectively antagonized RhlR; in contrast, it negligibly antagonized LasR only when applied at a high concentration. The exclusive RhlR antagonizing activity of curvularin at low concentrations was confirmed using QS mutants; specifically, curvularin at low concentrations inhibited pyocyanin and rhamnolipid production by selectively antagonizing N-butanoyl homoserine lactone (BHL)-activated RhlR. Moreover, by targeting RhlR, curvularin reduced the in vivo virulence of wild-type P. aeruginosa as well as lasR mutants in Caenorhabditis elegans. Overall, low-concentration curvularin is a pure RhlR antagonist in P. aeruginosa, and to the best of our knowledge, this is the first report describing an RhlR antagonist from natural resources. Hence, curvularin has great potential for the development of chronic P. aeruginosa infection therapeutics and for the study of RhlR function in the complex QS system.

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Section: Resultssupporting

confidence: 71%

Curvularin Isolated From Phoma macrostoma Is an Antagonist of RhlR Quorum Sensing in Pseudomonas aeruginosa

Choi

Kim

2022

Front. Microbiol.

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“…The structure of curvulone B was determined by 2D NMR spectroscopic and the absolute configuration was deduced by comparison of the experimental ECD spectra in acetonitrile with the Boltzman-averaged spectrum. 3 Total syntheses of curvulone B 2 have been reported by Takahashi et al, 2 Bates et al 4 and very recently by He et al, 5 none of them involving less than a ten linear step synthesis employing an intramolecular oxa-Michael addition for the formation of THP ring. Very recently, we reported the synthesis of 2,6-trans-disubstituted tetrahydropyrans with a keto functionality following a Mukaiyama-type aldol reaction of 1-phenyl-1triemthylsiloxyethylene with six membered cyclic hemiacetals in the presence of iodine.…”

Section: Figure 1 Structures Of Curvulone a (1) And Curvulone B (2)mentioning

confidence: 99%

“…3 Total syntheses of curvulone B (2) have been reported by the groups of Takahashi, 2 Bates, 4 and, more recently, He. 5 None of these syntheses involved fewer than ten linear steps, and all employed an intramolecular oxa-Michael addition for the formation of THP ring.…”

mentioning

confidence: 99%

Concise Total Synthesis of Curvulone B

Banoth

Choudhury

Marumudi

et al. 2020

Synlett

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A concise and convergent stereoselective synthesis of Curvulone B is described. The synthesis utilized the tandem isomerization followed by C-O and C-C bond forming reaction following Mukaiyama-type aldol conditions for the construction of trans-2,6-disubstituted dihydropyran ring system as the key step. Other important features of this synthesis are cross-metathesis, epimerization and Friedel-Crafts acylation reaction.

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“…Qi, Guo, He and teammates reported the synthesis of sumalactone A 195 , xestodecalactone A 196 , sumalactone B 197 , sumalactone C 198 , sumalactone D 199 , dehydrocurvularin 200 , and curvularin 201 (Scheme 14). [193] In their synthesis, RCM was one of the crucial steps and was employed at late‐stage steps to forge 11‐, 12‐, and 13‐membered rings. Herein, we have described only the synthesis of sumalactone A and also shown the structures of other sumalactone derivatives in the same Scheme.…”

Section: Ring‐closing Metathesis (Rcm)mentioning

confidence: 99%

“…). [193] In their synthesis, RCM was one of the crucial steps and was employed at late-stage steps to forge 11-, 12-, and 13-membered rings. Herein membered β-resorcylic macrolide extracted from fungus Fusarium sp.…”

Section: Total Synthesis Of Natural Products Based On Rcmmentioning

confidence: 99%

Metathesis Reactions in Natural Product Fragments and Total Syntheses

et al. 2022

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The passion of total‐ and fragments syntheses of natural products always remained one of the top priorities among the synthetic chemists worldwide. Due their curiosity toward the complexity of molecules of living nature and their endeavour to imitate them in laboratory; limitless arrays of natural products have been extracted, architecturally‐elucidated, synthesized, and chronicled by utilizing various synthetic methodologies in different fashions. Frequently, the synthesis of complex natural products proceed with inscrutable synthetic challenges, which can be circumvented either by modification of previously developed synthetic methods or by formulating a new one. In this way, a myriad of powerful synthetic reactions have been developed since the genesis of the logic of chemical synthesis. Amongst them, metathesis tactics discovered unexpectedly in the 1950s (Nobel Prize in 2005), have incredibly influenced and changed the landscape of the art of the total and formal synthesis in the last three A. H. Hoveyda, A. R. Zhugralin, me abruptly as compared to other developed transformations or their modified forms. In this particular review article, we envisioned to report a comprehensive detail of the metathetic tools involved in both total and fragments synthesis of natural products in the years 2018 and 2019 along with an overview of 2017.

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A Unified Synthetic Approach to Optically Pure Curvularin-Type Metabolites

Cited by 17 publications

References 41 publications

Curvularin Isolated From Phoma macrostoma Is an Antagonist of RhlR Quorum Sensing in Pseudomonas aeruginosa

Curvularin Isolated From Phoma macrostoma Is an Antagonist of RhlR Quorum Sensing in Pseudomonas aeruginosa

Concise Total Synthesis of Curvulone B

Metathesis Reactions in Natural Product Fragments and Total Syntheses

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