Naturally occurring tetramic acid products: isolation, structure elucidation and biological activity

Mo, Xuhua; Li, Qinglian; Ju, Jianhua

doi:10.1039/c4ra09047k

Cited by 145 publications

(117 citation statements)

References 216 publications

(496 reference statements)

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“…PTM compounds are structurally, biosynthetically, and pharmacologically unique natural products456. To date, there are approximately eleven PTM derivatives with a 5–6–5 ring system, including ikarugamycin ( 1 ) and capsimycin ( 2 ), which were previously isolated from Streptomyces 78910.…”

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confidence: 99%

“…The main skeleton consists of a carbocyclic ring system (rings A, B and C) and a 16-membered macrolactam ring (rings D and E)45. The usual post-modifications for rings A-C include epoxidation of the double bond at C-13/C-14 and oxidation of the side chain at C-30456. The other macrolactam modifications include hydroxylation at C-3 and methylation at N-28456.…”

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confidence: 99%

“…The usual post-modifications for rings A-C include epoxidation of the double bond at C-13/C-14 and oxidation of the side chain at C-30456. The other macrolactam modifications include hydroxylation at C-3 and methylation at N-28456. The broad diversity of PTM structures triggered our interest in investigating the biosynthetic connections within this group of metabolites.…”

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confidence: 99%

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Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Streptomyces xiamenensis 318 and post-modification via a novel cytochrome P450 monooxygenase

Jiang

et al. 2017

Sci Rep

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Polycyclic tetramate macrolactams (PTMs) were identified as distinct secondary metabolites of the mangrove-derived Streptomyces xiamenensis 318. Together with three known compounds—ikarugamycin (1), capsimycin (2) and capsimycin B (3)—two new compounds, capsimycin C (4) with trans-diols and capsimycin D (5) with trans-configurations at C-13/C-14, have been identified. The absolute configurations of the tert/tert-diols moiety was determined in 4 by NMR spectroscopic analysis, CD spectral comparisons and semi-synthetic method. The post-modification mechanism of the carbocyclic ring at C-14/C-13 of compound 1 in the biosynthesis of an important intermediate 3 was investigated. A putative cytochrome P450 superfamily gene, SXIM_40690 (ikaD), which was proximally localized to the ikarugamycin biosynthetic pathway, was characterized. In vivo gene inactivation and complementation experiment confirmed that IkaD catalysed the epoxide-ring formation reaction and further hydroxylation of ethyl side chain to form capsimycin G (3′). Binding affinities and kinetic parameters for the interactions between ikarugamycin (1) and capsimycin B (3) with IkaD were measured with Surface Plasmon Resonance. The intermediate compound 3′ was isolated and identified as 30-hydroxyl-capsimycin B. The caspimycins 2 and 3, were transferred to methoxyl derivatives, 6 and 7, under acidic and heating conditions. Compounds 1–3 exhibited anti-proliferative activities against pancreatic carcinoma with IC50 values of 1.30–3.37 μM.

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confidence: 99%

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Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Streptomyces xiamenensis 318 and post-modification via a novel cytochrome P450 monooxygenase

Jiang

et al. 2017

Sci Rep

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“…[90] Heute wird dieser sechszähnige Ligand in vielen häuslichen, industriellen und medizinischen Bereichen eingesetzt, insbesondere zur Desinfektion und Oberflächenreinigung.D ie bakteriostatischen Eigenschaften von Aminocarboxylat-Liganden, wie EDTAund DTPA ( 51) [82] Der dringende Bedarf an biologisch abbaubaren Alternativen hat zur Entwicklung von Ersatzstoffen, wie 51-54, geführt. [92] Sie bestehen aus Polyketiden und a-Aminosäuren und liegen normalerweise als Mischung aus sich ineinander umwandelnden Rotameren und Tautomeren vor. Außerdem ist 53 wirksamer bei der Erhçhung der Wirksamkeit antimikrobieller Substanzen durch Erhçhung der Permeabilitätd er bakteriellen Membran.…”

Section: Angewandte Chemieunclassified

Chemische und biologische Aspekte von “Nutritional Immunity” – Perspektiven für neue Antiinfektiva mit Fokus auf bakterielle Eisenaufnahmesysteme

et al. 2017

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Eine der Verteidigungsstrategien eines Wirtes gegen bakterielle Infektionen ist der Entzug essentieller Metallionen, insbesondere von Eisenionen, durch Komplexierung. Dies wird als Nährstoffimmunität (“nutritional immunity”) bezeichnet. Bakterien haben jedoch Strategien zur Anpassung an den Eisenmangel entwickelt. Sie “stehlen” zum Beispiel Eisen vom Wirt oder von anderen Bakterien durch spezifische Chelatoren mit einer hohen Affinität für Eisen. Die komplexen Wechselwirkungen zwischen Wirt und Pathogen zur Homöostase von Metallionen bieten zahlreiche Angriffspunkte für die Entwicklung neuer antibakterieller Wirkstoffe. Dieser Aufsatz ist auf Prozesse mit Eisenbeteiligung fokussiert. Es werden die neuesten Entwicklungen und mögliche Perspektiven für die Entwicklung von Antibiotikaresistenzen diskutiert.

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“…One iron chelator moiety that appears to be underutilized is the class of natural products known as tetramic acids. Tetramic acid motifs are found in a wide variety of pharmacologically active natural products, with many displaying antifungal and antibacterial activities [13–15]. Molecules bearing the tetramic acid core demonstrate diverse modes of action ranging from inhibition of cell wall [16] and RNA synthesis [17] and dissipation of the membrane potential [18].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and microbiological evaluation of ampicillin–tetramic acid hybrid antibiotics

et al. 2016

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Exploiting iron-uptake pathways by conjugating β-lactam antibiotics with iron-chelators such as catechol and hydroxamic acid is a proven strategy to overcome permeability-related resistance in Gram-negative bacteria. Since naturally occurring iron chelating tetramic acids have not been previously examined for this purpose, an exploratory series of novel ampicillin-tetramic acid hybrids that structurally resemble ureidopenicillins was designed and synthesized. The new analogs were evaluated for the ability to chelate iron and their MIC activities determined against a representative panel of clinically significant bacterial pathogens. The tetramic acid β-lactam hybrids demonstrated a high affinity to iron in the order of 10−30 M3. The hybrids were less active against Gram-positive bacteria. However, against Gram-negative bacteria, their activity was species dependent with several hybrids displaying improved activity over ampicillin against wild-type Pseudomonas aeruginosa. The anti-Gram-negative activities of the hybrids improved in the presence of clavulanic acid revealing that the tetramic acid moiety did not provide added protection against β-lactamases. Additionally, the hybrids were found to be efflux pump substrates as their activities markedly improved against pump-inactivated strains. Unlike the catechol and hydroxamic acid siderophore β-lactam conjugates, the activities of the hybrids did not improve under iron-deficient conditions. These results suggest that the tetramic acid hybrids gain permeability via different membrane receptors, or they are out competed by native bacterial siderophores with stronger affinities for iron. This study provides a foundation for the further exploitation of the tetramic acid moiety to achieve novel β-lactam anti-Gram-negative agents, providing that efflux and β-lactamase mediated resistance is addressed.

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Naturally occurring tetramic acid products: isolation, structure elucidation and biological activity

Abstract: Natural products containing the tetramic acid core scaffold have been isolated from an assortment of terrestrial and marine species and often display wide ranging and potent biological activities including antibacterial, antiviral and antitumoral activities.

Cited by 145 publications

References 216 publications

Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Streptomyces xiamenensis 318 and post-modification via a novel cytochrome P450 monooxygenase

Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Streptomyces xiamenensis 318 and post-modification via a novel cytochrome P450 monooxygenase

Chemische und biologische Aspekte von “Nutritional Immunity” – Perspektiven für neue Antiinfektiva mit Fokus auf bakterielle Eisenaufnahmesysteme

Design, synthesis and microbiological evaluation of ampicillin–tetramic acid hybrid antibiotics

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