Maßgeschneiderte Ahp‐Cyclodepsipeptide als potente, nicht‐kovalente Serinprotease‐Inhibitoren

Köcher, Steffen; Rey, Juliana; Bongard, Jens; Tiaden, André N.; Meltzer, Michael; Richards, Peter J.; Ehrmann, Michael; Kaiser, Markus

doi:10.1002/ange.201701771

Cited by 3 publications

(2 citation statements)

References 33 publications

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“…[42] This protocol is especially suited for the stereoselectivef ormationo fsyn g,d-unsaturated amino acids either from simple chiral allylic alcohols, [43,44] or in the presence of chiral ligands. [50] Maskingt he resulting alcohol as TBS ether yielded 16, [51] subsequent saponification and N-methylation generated N-methyl-d-hydroxyn orvaline 18 almostq uantitativelyo nagram scale. [47,48] While separation by distillation due to the similarv olatility of the undesired (R)-acetate and enantiomericallye nriched (S)-alcohol failed, the mixture was directly subjected to Steglich esterification [49] with Alloc-Gly-OH (12).…”

Section: Resultsmentioning

confidence: 99%

“…Inspired by Kaiser et al we startedt he fragment synthesis with protected glutamic acid 15,w hich was first activated as mixed anhydridea nd then reduced by NaBH 4 (Scheme 3). [50] Maskingt he resulting alcohol as TBS ether yielded 16, [51] subsequent saponification and N-methylation generated N-methyl-d-hydroxyn orvaline 18 almostq uantitativelyo nagram scale.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

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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Structural Diversity and Anticancer Activity of Marine‐Derived Elastase Inhibitors: Key Features and Mechanisms Mediating the Antimetastatic Effects in Invasive Breast Cancer

2018

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Three new 3-amino-6-hydroxy-2-piperidone (Ahp)-containing cyclic depsipeptides, named loggerpeptins A-C (1-3), along with molassamide (4), were discovered from a marine cyanobacterium, extending the structural diversity of this prevalent scaffold of cyanobacterial serine protease inhibitors. Molassamide, which contains a 2-amino-butenoic (Abu) unit in the cyclic core, was the most potent and selective analogue against human neutrophil elastase (HNE). Given the growing evidence supporting the role of HNE in breast cancer progression and metastasis, we assessed the cellular effects of compounds 3 and 4 in the context of targeting invasive breast cancer. Both compounds inhibited cleavage of the elastase substrate CD40 in biochemical assays; however, only 4 exhibited significant cellular activity. As CD40 and other receptor proteolytic processing culminates in NFκB activation, we assessed the effects of 4 on the expression of target genes, including ICAM-1. ICAM-1 is also a direct target of elastase and, in our studies, compound 4 attenuated both elastase-induced ICAM-1 gene expression and ICAM-1 proteolytic processing by elastase, revealing a potential dual effect on migration through modulation of gene expression and proteolytic processing. Molassamide also specifically inhibited the elastase-mediated migration of highly invasive triple-negative breast cancer cells.

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Zelkovamycin is an OXPHOS Inhibitory Member of the Argyrin Natural Product Family

Krahn

Heilmann

Vogel

et al. 2020

Chemistry A European J

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Natural products (NPs) are an important inspirational source for developing drugs and chemical probes. In 1999, the group of Ō mura reportedt he constitutional elucidation of zelkovamycin. Although largely unrecognized so far,t his NP displays structural similarities as well as differences to the argyrin NP family, ac lass of peptidic NPs with promising anticancer activities and diverse mode-of-action at the molecular level. By ac ombination of structure elucidation experiments, the first total synthesis of zelkovamycin and bioassays, the zelkovamycin configuration was determined and its previously proposed molecular structure was revised. The full structure assignment provesz elkovamycin as an additional member of the argyrins with however unique OXPHOSi nhibitory properties. Zelkovamycin may therefore not only serve as an ew startingp oint for chemical inhibitors of the OXPHOSs ystem,b ut also guide customized argyrin NP isolationa nd biosynthesis studies.

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Maßgeschneiderte Ahp‐Cyclodepsipeptide als potente, nicht‐kovalente Serinprotease‐Inhibitoren

Cited by 3 publications

References 33 publications

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

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

Structural Diversity and Anticancer Activity of Marine‐Derived Elastase Inhibitors: Key Features and Mechanisms Mediating the Antimetastatic Effects in Invasive Breast Cancer

Zelkovamycin is an OXPHOS Inhibitory Member of the Argyrin Natural Product Family

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