Abstract
The Ascomycota Dichotomomyces cejpii was isolated from the marine sponge Callyspongia cf. C. flammea. A new gliotoxin derivative, 6-acetylmonodethiogliotoxin (1) was obtained from fungal extracts. Compounds 2 and 3, methylthio-gliotoxin derivatives were formerly only known as semi-synthetic compounds and are here described as natural products. Additionally the polyketide heveadride (4) was isolated. Compounds 1, 2 and 4 dose-dependently down-regulated TNFα-induced NF-κB activity in human chronic myeloid leukemia cells with IC50s of 38.5 ± 1.2 µM, 65.7 ± 2.0 µM and 82.7 ± 11.3 µM, respectively. The molecular mechanism was studied with the most potent compound 1 and results indicate downstream inhibitory effects targeting binding of NF-κB to DNA. Compound 1 thus demonstrates potential of epimonothiodiketopiperazine-derived compounds for the development of NF-κB inhibitors.
Highlights
The secondary metabolism of fungi gives rise to chemically most diverse structures, some of which have proven useful in drug development
In the present study we investigated the inhibitory effect of newly isolated natural epipolythiodiketopiperazines on anti-proliferative mechanisms via TNFα-induced p50/p65 NF-κB
Compound 1 was obtained from the marine sponge-derived fungus D. cejpii and its structure was elucidated via intensive analysis of spectroscopic data
Summary
The secondary metabolism of fungi gives rise to chemically most diverse structures, some of which have proven useful in drug development. A promising source for new secondary metabolites are organisms isolated from special habitats, like marine-derived fungi and bacteria [1]. Fungal secondary metabolites have gained popularity due to their newly discovered pharmaceutical potential as anti-inflammatory, cytotoxic or cytostatic agents. These marine-derived drug candidates display epigenetic and anti-cancer activities against P388 murine leukemia cells. Compounds containing a disulfide bond including gliotoxin G, 5a,6-didehydrogliotoxin and gliotoxin showed potent in vitro inhibitory activity against the recombinant H3K9 histone methyl transferase G9a. The presence of a disulfide bond is usually accompanied by distinct toxic effects that limit the therapeutic usage of this compound group
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
