Glucopiericidin C: a cytotoxic piericidin glucoside antibiotic produced by a marine Streptomyces isolate

Abstract

More than 35 naturally occurring piericidins 1,2 and closely related antibiotics 3,4 have been reported. They are derived from prenylated polyoxypyridines and exhibit interesting biological activities. Among them, glucopiericidin A (1), B and some others display antimicrobial properties and in vitro inhibitory activity against antibody formation. 5 For glucopiericidiols A1 and A2, additional cytocidal activities against HeLa S3 cells in vitro have been reported, 6 and others demonstrate insecticidal activity. 7 The biological activities of the glucopiericidins are strongly influenced by the structure and position of the sugar unit: glucopiericidins A (1) and B show higher antimicrobial activities than piericidin A (2) or other glycosides such as 3¢-rhamnopiericidin A1 (SN-198-C), 8 3¢-deoxytalopiericidin A1 (DTPA) 9 and 7-demethyl-3¢-rhamnopiericidin A1. 10 In contrast, acute toxicities of the latter three substances in mice were lower than those of piericidin A (2). 5 In our search for new secondary metabolites from marine bacteria, we isolated a new cytotoxic piericidin derivative, glucopiericidin C (3), and for the first time as natural product, 5-oxo-5-o-tolyl-pentanoic acid (8a) together with further 10 known metabolites. The algal metabolite spatozoate (6) was isolated here for the first time from bacteria.The crude extract obtained by fermentation of the marine-derived Streptomyces isolate B8112 was moderately active against Grampositive and Gram-negative bacteria and Candida albicans, but strongly active against the fungus Mucor miehei (Tü284). Additionally, a pronounced in vitro antitumor activity with a mean IC 70 of o10 mg ml À1 was found in a six cell line panel. 11 TLC of the extract exhibited numerous UV absorbing bands: two of them (3, 6) turned blue with anisaldehyde/sulfuric acid and later to dark green in the case of 3, whereas 8a changed to purple on standing.For preparative isolation, the strain was cultivated on M 2 + medium as a shake culture at 28 1C for 7 days, and extracted as reported previously. 12 Chromatography on Sephadex LH-20 (Lipophilic Sephadex, Amersham Bioscience, purchased from Sigma-Aldrich Chemie, Steinheim, Germany) led to the isolation of indole-3-carboxylic acid and uracil; flash silica gel column chromatography of fraction I delivered five subfractions (SFs) ABE. Purification of the less polar SF A led to spatozoate (6). Further purification of SF C on Sephadex LH-20 gave 5-(2-methylphenyl)-4-pentenoic acid) (7) 13 and monensin B, 14,15 whereas the middle polar SF D afforded 5-oxo-5-o-tolylpentanoic acid (8a), along with glucopiericidin A (1), 6 piericidin A (2) 5,16 and phenylacetic acid. Separation of the most polar SF E by PTLC, followed by chromatography on Sephadex LH-20, gave glucopiericidin C (3), 2¢-deoxy-uridin and 2¢-deoxy-thymidin. The known compounds were identified by means of their NMR and mass data using AntiBase, 2 and by comparison with authentic spectra.The physicochemical properties of compound 3 are summarized in Table 1. The UV data and the proton N...

Piericidins, Novel Quorum-Sensing Inhibitors against Chromobacterium violaceum CV026, from Streptomyces sp. TOHO-Y209 and TOHO-O348

“…[24][25][26][27]. Although S. aburaviensis and S. phaeofaciens are not reported to produce piericidin A1, 3'-rhamnopiericidin A1, or piericidin E, Streptomyces sp.…”

The unique chemistry and biology of the piericidins

“…Although soil-derived actinomycetes have been the predominant source of the piericidins, more recently, marine-derived Streptomyces isolates have shown promise to produce piericidins, especially new piericidin analogs. 24,33 Piericidins are well known as complex I inhibitors. Moreover, some piericidins, such as 3′-deoxytalopiericidin-A1(39) 32 and piericidin B1 N-oxide (18), are promising as lead compounds for anti-cancer drug development.…”

“…71 In the acute toxicity tests administering piericidin A (1) by i.v. administration in mice, the LD 50 value was o1.0 mg kg −1 , 28,72 whereas glucopiericidins A (32) and B (33) showed less toxicity with LD 50 values between 10 and 30 mg kg − 1 . Most of the other piericidins, including the glycosides, also showed cytotoxic activities to several cancer cell lines ( Table 1).…”

“…Glucopiericidins A-C (32, 33 and 40) showed higher antimicrobial activities than piericidin A (1) or other glycoside analogs. 28,33 It was interesting that the glycosides 3'-rhamnopiericidin A1 (37) and 7-demethyl-3′-rhamnopiericidin A1 (38) showed lower antimicrobial activities against some fungi and Gram-negative bacteria than 7-demethylpiericidin A1 (30) and piericidin A (1). In contrast, 37 and 38 showed stronger cytotoxicity against KB and K562 cells.…”

“…Glucoside 40 was similar to glucopiericidin A, except for the loss of the methoxy group at C-3′ ( Figure 4). 33 …”