A new furaquinocin derivative, JBIR-136, from Streptomyces sp. 4963H2

Abstract

Natural products are considered to be good sources for the screening of lead compounds of clinical drugs. We performed a large number of drug screenings by using a variety of assay systems with crude extracts of microbial cultures as a traditional natural product library. In some assay systems, our crude extract library could not work effectively. With this in mind, we started to construct a purified natural compound library possessing various skeletons from cultures of microorganisms. As actinomycetes are known to produce pharmaceutically useful compounds, 1,2 we focused mainly on secondary metabolites from cultures of actinomycetes. To achieve this, we established a high-throughput system for the detection of secondary metabolites from the cultures of actinomycetes with the retentiontime and HR-MS data of known compounds by using a UPLC-TOF-MS system (Waters, Milford, MA, USA). 3 We analyzed the secondary metabolites, including potential novel compounds, present in the cultures of the strains isolated from a variety of resources by this system. 3 In the course of our chemical screening program, a new furaquinocin derivative named JBIR-136 (1, Figure 1a), together with the known compound kujimycin A, 4 was isolated from a culture broth of Streptomyces sp. 4963H2. This paper describes the fermentation, isolation, structural elucidation and, in brief, the biological activity of 1.Streptomyces sp. 4963H2 was isolated from a soil sample collected in Kimitsu, Chiba Prefecture, Japan. The strain was cultivated in 50-ml test tubes, each containing 15 ml of a seed medium consisting of 1.0% starch (Kosokagaku, Tokyo, Japan), 1.0% polypeptone (Nihon Pharmaceutical, Tokyo, Japan), 1.0% molasses (Dai-Nippon Meiji Sugar, Tokyo, Japan) and 1.0% meat extract (Extract Ehlrich, Wako Pure Chemical Industry, Osaka, Japan) at pH 7.2 (adjusted before sterilization). The test tubes were shaken on a reciprocal shaker (320 r.p.m.) at 27 1C for 2 days. Aliquots (2.5 ml) of the broth were transferred to 500-ml baffled Erlenmeyer flasks containing 100 ml of a production medium consisting of 2.0% glycerol (Nacalai Tesque, Kyoto, Japan), 1.0% molasses (Dai-Nippon Meiji Sugar), 0.5% casein (Kanto Chemical, Tokyo, Japan), 0.1% polypeptone (Nihon Pharmaceutical) and 0.4% CaCO 3 (Kozaki Pharmaceutical, Tokyo, Japan) at pH 7.2 (adjusted before sterilization), and were cultured on a rotary shaker (180 r.p.m.) at 27 1C for 5 days.The fermentation broth (2 l) was separated by centrifugation. The supernatant was partitioned between EtOAc and H 2 O (2l 3), whereas the mycelial cake was extracted with acetone (50 ml) and filtered, and the filtrate was concentrated in vacuo. The residual aqueous concentrate was extracted with EtOAc (equal volume  3). The combined EtOAc layers were dried over Na 2 SO 4 , and then evaporated to dryness. The residue (733 mg) was subjected to normalphase medium pressure liquid chromatography (Purif-Pack SI-30, Shoko Scientific, Yokohama, Japan) and developed successively with a gradient system of n-hexane-EtOAc (0-15% E...

Marine natural products

“…230 An OSMAC approach to cultivation of Penicillium aurantiogriseum (mud, Bohai Sea, China) resulted in production of the auranomides A-C 242-244. 231 P. citrinum (unidentied sponge, Ishigaki Is., Okinawa, Japan) was the source of JBIR-124 245, a DPPH radical scavenger, 232 Communols A-G 256-262 are aromatic polyketides isolated from P. commune (gorgonian Muricella abnormalis, Danzhou, Hainan, China), of which communols A, F and G were moderately active against E. coli and Enterobacter aerogenes (E. aerogenes). 236,237 Penilactones A 263 and B 264 are highly oxygenated polyketides from P. crustosum (deep sea sediment, Prydz Bay, Antarctica).…”

Fungal natural products in research and development

“…192 The sorbicillin dimer, dihydrotrichodermolide (194), the sorbicillin monomer dihydromethylsorbicillin (195), and the benzofuran phialofurone (196) exhibited cytotoxic activity against the P388 cell line with IC 50 values of 11.5 mM, 0.1 mM, and 0.2 mM respectively. The sorbifuranones A, B, and C (196)(197)(198) were isolated from Penicillium strains derived from Mediterranean sponges. 193 These structures are a new class of sorbicillinol-derivatives.…”

Copper and Manganese Cations Alter Secondary Metabolism in the FungusPenicillium brasilianum

“…Compound 1 was identified as the cyclodepsipeptide JBIR 113 already described by Kawahara et al, 14 which was produced by a marine sponge-derived Penicillium sp. fS36 isolated in Japan and was co-produced to other two cyclodepsipeptides JBIR 114 and JBIR 115 that differentiates in the composition and sequence of the amino-acid residues 13 ( Figure 5).…”