Caspase-1 Inhibitors from an Extremophilic Fungus That Target Specific Leukemia Cell Lines

Abstract

Berkeley Pit Lake, Butte, Montana is a 540 m. deep abandoned open-pit copper mine filled with over 140 billion liters of acidic, metal-sulfate contaminated water. This harsh environment has yielded several microorganisms that produce interesting biologically active compounds. Several polyketide metabolites including the new berkazaphilones A (1) and B (2) and octadienoic acid derivatives berkedienoic acid (13) and berkedienolactone (15), as well as previously reported azaphilone 4, vermistatin (6), dihydrovermistatin (7), penisimplicissin (8), aldehyde 9 and methyl paraconic acid (11) were isolated from a culture broth of Penicillium rubrum taken from a depth of 270 m. The structures of these compounds were deduced by interpretation of spectroscopic data. The compounds were isolated either for their inhibition of the signal transduction enzyme caspase-1 or because of their structural similarity to these inhibitors. Selected compounds were further evaluated for their ability to inhibit interleukin-1β production by inflammasomes in induced THP-1 cells. Berkazaphilone B (2) and C (4) and vermistatin analogue penisimplicissin (8) exhibited selective activity against leukemia cancer cell lines in the National Cancer Institute 60 human cell line assay.

Oxoberkedienoic acid: a new octadienoic acid derivative isolated from <i>Talaromyces verruculosus</i> using a chemical screening system

“…The IR spectrum showed characteristic absorptions at 3432 and 1639 cm -1 , suggesting the presence of hydroxyl and carbonyl groups. Comparing with the reported NMR and MS data, the structure of 1 was suggested to be similar to that of berkedienoic acid, which was originally isolated as a octadienoic acid derivative from the fermentation broth of Penicillium rubrum (Stierle et al, 2012). The structure of 1 was mainly elucidated by NMR, including 2D NMR.…”

Bioactive Secondary Metabolites from Acid Mine Waste Extremophiles

“…Compounds 25 - 30 also inhibited the production of IL-1β in THP-1 cells at a concentration of 200 μg/mL. However, berkazaphilone B ( 26 ) was completely inhibitory at 2.0 μg/mL, and berkazaphilone C ( 27 ) at 20 μg/mL [43]. These data will be shown in a later section.…”

“…P. rubrum also produced berkazaphilones A-C ( 25 - 27 ), vermistatin ( 28 ), dihydrovermistatin ( 29 ), and penisimplicissin ( 30 ) [43]. Of the azaphilone analogs reviewed, only one other compound, pseudohalonectrin, was not oxygenated at C-7 [44].…”

Vermistatin Derivatives with α-Glucosidase Inhibitory Activity from the Mangrove Endophytic Fungus Penicillium sp. HN29-3B1

“…In fungi, polyketide metabolites are one important group of secondary metabolites, possess a wide range of biological activities, and give rise to a myriad of diverse structures [3,4]. Vermistatin derivatives are a typical example of polyketides, which have been reported to have a variety of biological activities including antifungal, antibacterial, antitumor, cytotoxic [5,6], and caspase-1 inhibitory activities [7,8]. However, inhibition of α-glucosidase remains underexplored as a potential resource of new bioactive natural products.…”

“…5 were further separated by silica gel CC and Sephadex LH-20 CC to give compounds 1-8. The structures of 4-8 were established as methoxyvermistatin (4) [5], vermistatin (5) [13], 6-demethylvermistatin (6) [7], hydroxyvermistatin (7) [5], and penisimplicissin (8) [14] by comparison of their NMR and MS data with those previously reported. The absolute configuration of compound 5 was further confirmed by a single-crystal X-ray diffraction experiment using Cu Kα radiation with a Flack parameter of 0.02(10) [15].…”