Natural products as probes in pharmaceutical research

Schmitt, E.; Hoepfner, Dominic; Krastel, Philipp

doi:10.1007/s10295-015-1691-9

Cited by 19 publications

(16 citation statements)

References 62 publications

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“…This could explain why NPs and NDs constitute almost the two third of anticancer, immunosuppressive, antibacterial, anticoagulant, antifungal and antiparasitic drugs [9]. NPs display a large chemodiversity [10] and play a key role in pharmaceutical research: they could be structural leads of new drugs [9] as well as a way to investigate new biological pathways and to discover new therapeutic targets [11]. We previously reported on the potential of secondary metabolites from Clusiaceous and Calophyllaceous species to reduce endothelial dysfunctions [12, 13].…”

Section: Introductionmentioning

confidence: 99%

Prenylated Polyphenols from Clusiaceae and Calophyllaceae with Immunomodulatory Activity on Endothelial Cells

et al. 2016

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Endothelial cells (ECs) are key players in inflammation and immune responses involved in numerous pathologies. Although attempts were experimentally undertaken to prevent and control EC activation, drug leads and probes still remain necessary. Natural products (NPs) from Clusiaceous and Calophyllaceous plants were previously reported as potential candidates to prevent endothelial dysfunction. The present study aimed to identify more precisely the molecular scaffolds that could limit EC activation. Here, 13 polyphenols belonging to 5 different chemical types of secondary metabolites (i.e., mammea coumarins, a biflavonoid, a pyranochromanone acid, a polyprenylated polycyclic acylphloroglucinol (PPAP) and two xanthones) were tested on resting and cytokine-activated EC cultures. Quantitative and qualitative changes in the expression of both adhesion molecules (VCAM-1, ICAM-1, E-selectin) and major histocompatibility complex (MHC) molecules have been used to measure their pharmaceutical potential. As a result, we identified 3 mammea coumarins that efficiently reduce (up to >90% at 10 μM) both basal and cytokine-regulated levels of MHC class I, class II, MICA and HLA-E on EC surface. They also prevented VCAM-1 induction upon inflammation. From a structural point of view, our results associate the loss of the free prenyl group substituting mammea coumarins with a reduced cellular cytotoxicity but also an abrogation of their anti-inflammatory potential and a reduction of their immunosuppressive effects. A PPAP, guttiferone J, also triggers a strong immunomodulation but restricted to HLA-E and MHC class II molecules. In conclusion, mammea coumarins with a free prenyl group and the PPAP guttiferone J emerge as NPs able to drastically decrease both VCAM-1 and a set of MHC molecules and to potentially reduce the immunogenicity of the endothelium.

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Section: Introductionmentioning

confidence: 99%

Prenylated Polyphenols from Clusiaceae and Calophyllaceae with Immunomodulatory Activity on Endothelial Cells

et al. 2016

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“…HOP (both gene copies deleted) reveals synthetic lethality and identifies compensating pathways. Large-scale datasets as well as numerous individual applications of this approach have been published showing the impact and elegance of the approach 2 3 4 . However, due to the dependency on genome-wide, bar-coded deletion collections this approach has been mainly limited to S. cerevisiae .…”

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confidence: 99%

Identification of a novel NAMPT inhibitor by CRISPR/Cas9 chemogenomic profiling in mammalian cells

Estoppey

Hewett

Guy

et al. 2017

Sci Rep

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Chemogenomic profiling is a powerful and unbiased approach to elucidate pharmacological targets and the mechanism of bioactive compounds. Until recently, genome-wide, high-resolution experiments of this nature have been limited to fungal systems due to lack of mammalian genome-wide deletion collections. With the example of a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, we demonstrate that the CRISPR/Cas9 system enables the generation of transient homo- and heterozygous deletion libraries and allows for the identification of efficacy targets and pathways mediating hypersensitivity and resistance relevant to the compound mechanism of action.

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“…Es-pecially pathogens known to develop mutations causing multiple drugr esistance (MDR) like Mycobacterium tuberculosis (Mtb) are only controllable by innovative drugs with new modes of action, preferably addressing new biological targets. [10][11][12][13][14][15] As mall family of cyclopeptides, isolated from the marine streptomycete strain CNB-982, the cyclomarina A-C, [16] represent ac lass of natural products with ar emarkable antibacterial activity against Mtb (Figure 1). [6][7][8][9] Thus, natural products take a firm place in drug discovery, either as directd rug candidates or as lead structures.…”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8][9] Thus, natural products take a firm place in drug discovery, either as directd rug candidates or as lead structures. [10][11][12][13][14][15] As mall family of cyclopeptides, isolated from the marine streptomycete strain CNB-982, the cyclomarina A-C, [16] represent ac lass of natural products with ar emarkable antibacterial activity against Mtb (Figure 1). [17] The mayor metabolite cyclomarin Ae xhibits antituberculara ctivity against both growing and hypoxicn on-replicatingi ntracellular mycobacteria in human-derivedmacrophagesi nt he low micromolar range.…”

Section: Introductionmentioning

confidence: 99%

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

Kiefer

Bader

Held

et al. 2019

Chemistry A European J

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Cyclomarins are highly potent antimycobacterial and antiplasmodial cyclopeptides isolated from am arine bacterium (Streptomyces sp.). Previous studies have identified the targetp roteins and elucidated an ovel mode of action,h owever there are currently only af ew studies examining the structure-activity relationship (SAR) for both pathogens. Herein, we report the synthesisa nd biological evaluation of 17 novel desoxycyclomarin-inspired analogues. Optimization via side chain modificationso ft he non-canonical amino acids led to potentl ead structures for each pathogen. Figure 1. Structure diversity of cyclomarins.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

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Natural products as probes in pharmaceutical research

Cited by 19 publications

References 62 publications

Prenylated Polyphenols from Clusiaceae and Calophyllaceae with Immunomodulatory Activity on Endothelial Cells

Prenylated Polyphenols from Clusiaceae and Calophyllaceae with Immunomodulatory Activity on Endothelial Cells

Identification of a novel NAMPT inhibitor by CRISPR/Cas9 chemogenomic profiling in mammalian cells

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

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