Synthesis of New Cyclomarin Derivatives and Their Biological Evaluation towards <i>Mycobacterium Tuberculosis</i> and <i>Plasmodium Falciparum</i>

Kiefer, Alexander F.; Bader, Chantal D.; Held, Jana; Esser, Anna; Rybniker, Jan; Empting, Martin; Müller, Rolf; Kazmaier, Uli

doi:10.1002/chem.201901640

Cited by 25 publications

(26 citation statements)

References 74 publications

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Section: Resultsmentioning

confidence: 99%

“…The antifungal lipopeptide mycosubtilin, which is used for the biocontrol of the Pythium aphanidermatum pathogen in tomato seedlings [75]. Cyclomarin, which is a highly potent antimycobacterial and antiplasmodial cyclopeptides [76] (Figure 4A). The taxonomic group with the highest number of catalytic domains identified were Proteobacteria with almost 68% of the sequences, followed by Firmicutes with 13% of sequences identified.…”

Section: Metatrancriptomics Identification Of Nrpssmentioning

confidence: 99%

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Mining the Yucatan Coastal Microbiome for the Identification of Non-Ribosomal Peptides Synthetase (NRPS) Genes

Martínez-Núñez

Rodríguez-Escamilla

2020

Toxins

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Prokaryotes represent a source of both biotechnological and pharmaceutical molecules of importance, such as nonribosomal peptides (NRPs). NRPs are secondary metabolites which their synthesis is independent of ribosomes. Traditionally, obtaining NRPs had focused on organisms from terrestrial environments, but in recent years marine and coastal environments have emerged as an important source for the search and obtaining of nonribosomal compounds. In this study, we carried out a metataxonomic analysis of sediment of the coast of Yucatan in order to evaluate the potential of the microbial communities to contain bacteria involved in the synthesis of NRPs in two sites: one contaminated and the other conserved. As well as a metatranscriptomic analysis to discover nonribosomal peptide synthetases (NRPSs) genes. We found that the phyla with the highest representation of NRPs producing organisms were the Proteobacteria and Firmicutes present in the sediments of the conserved site. Similarly, the metatranscriptomic analysis showed that 52% of the sequences identified as catalytic domains of NRPSs were found in the conserved site sample, mostly (82%) belonging to Proteobacteria and Firmicutes; while the representation of Actinobacteria traditionally described as the major producers of secondary metabolites was low. It is important to highlight the prediction of metabolic pathways for siderophores production, as well as the identification of NRPS’s condensation domain in organisms of the Archaea domain. Because this opens the possibility to the search for new nonribosomal structures in these organisms. This is the first mining study using high throughput sequencing technologies conducted in the sediments of the Yucatan coast to search for bacteria producing NRPs, and genes that encode NRPSs enzymes.

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Section: Resultsmentioning

confidence: 99%

Section: Metatrancriptomics Identification Of Nrpssmentioning

confidence: 99%

Mining the Yucatan Coastal Microbiome for the Identification of Non-Ribosomal Peptides Synthetase (NRPS) Genes

Martínez-Núñez

Rodríguez-Escamilla

2020

Toxins

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“…Under acidic conditions, water is rapidly eliminated, resulting in the formation of the α,β-unsaturated dehydrotryptophan derivative. To avoid these problems, Kazmaier et al synthesized a series of cyclomarin derivatives containing non-hydroxylated tryptophans (desoxycyclomarins), e.g., the building blocks found in ilamycins/rufomycin [ 85 , 86 ]. N -Isopropyltryptophan was obtained via Negishi coupling of 3-iodo- N -isopropylindole with protected zincated iodoalanine [ 86 ].…”

Section: Syntheses Of Cyclomarin Derivativesmentioning

confidence: 99%

“…To avoid these problems, Kazmaier et al synthesized a series of cyclomarin derivatives containing non-hydroxylated tryptophans (desoxycyclomarins), e.g., the building blocks found in ilamycins/rufomycin [ 85 , 86 ]. N -Isopropyltryptophan was obtained via Negishi coupling of 3-iodo- N -isopropylindole with protected zincated iodoalanine [ 86 ]. Other derivatives can be obtained by an improved protocol for tryptophan alkylations [ 81 ].…”

Section: Syntheses Of Cyclomarin Derivativesmentioning

confidence: 99%

Recent Developments on the Synthesis and Bioactivity of Ilamycins/Rufomycins and Cyclomarins, Marine Cyclopeptides That Demonstrate Anti-Malaria and Anti-Tuberculosis Activity

Kazmaier

Junk

2021

Marine Drugs

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Ilamycins/rufomycins and cyclomarins are marine cycloheptapeptides containing unusual amino acids. Produced by Streptomyces sp., these compounds show potent activity against a range of mycobacteria, including multidrug-resistant strains of Mycobacterium tuberculosis. The cyclomarins are also very potent inhibitors of Plasmodium falciparum. Biosynthetically the cyclopeptides are obtained via a heptamodular nonribosomal peptide synthetase (NRPS) that directly incorporates some of the nonproteinogenic amino acids. A wide range of derivatives can be obtained by fermentation, while bioengineering also allows the mutasynthesis of derivatives, especially cyclomarins. Other derivatives are accessible by semisynthesis or total syntheses, reported for both natural product classes. The anti-tuberculosis (anti-TB) activity results from the binding of the peptides to the N-terminal domain (NTD) of the bacterial protease-associated unfoldase ClpC1, causing cell death by the uncontrolled proteolytic activity of this enzyme. Diadenosine triphosphate hydrolase (PfAp3Aase) was found to be the active target of the cyclomarins in Plasmodia. SAR studies with natural and synthetic derivatives on ilamycins/rufomycins and cyclomarins indicate which parts of the molecules can be simplified or otherwise modified without losing activity for either target. This review examines all aspects of the research conducted in the syntheses of these interesting cyclopeptides.

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“…A similar protocol was used in the synthesis of a building block, in the preparation of Cyclomarins 7, novel antimalarial and antitubercular agents (Figure 1). 11 In the total synthesis of Chlamydocin 8, a cyclic peptide showing histone deacetylase (HDAc) inhibition, the chelated Claisen reaction was one of the key steps (Figure 1). 12 The discussed procedure can also be applied to N-protected allylic esters of α,β-unsaturated amino acids 9 (Table 2).…”

Section: Chelated Claisen Rearrangementmentioning

confidence: 99%

Synthesis of γ,δ-unsaturated amino acids by Claisen rearrangement - last 25 years

Bilska-Markowska¹,

Kaźmierczak²,

Koroniak³

2020

Arkivoc

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This mini review summarizes achievements in the synthesis of y,δ-unsaturated amino acids via Claisen rearrangements. The multitude of products that can be obtained using the discussed protocol shows that it is one of the most important reactions in organic synthesis. Moreover, many Claisen rearrangement products are building blocks in the synthesis of more complex molecules with potential biological activity.

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Synthesis of New Cyclomarin Derivatives and Their Biological Evaluation towards Mycobacterium Tuberculosis and Plasmodium Falciparum

Cited by 25 publications

References 74 publications

Mining the Yucatan Coastal Microbiome for the Identification of Non-Ribosomal Peptides Synthetase (NRPS) Genes

Mining the Yucatan Coastal Microbiome for the Identification of Non-Ribosomal Peptides Synthetase (NRPS) Genes

Recent Developments on the Synthesis and Bioactivity of Ilamycins/Rufomycins and Cyclomarins, Marine Cyclopeptides That Demonstrate Anti-Malaria and Anti-Tuberculosis Activity

Synthesis of γ,δ-unsaturated amino acids by Claisen rearrangement - last 25 years

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