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A marine-derived fungus of the genus Stachylidium was isolated from the sponge Callyspongia cf. C. flammea. Chemical investigation of the bioactive fungal extract led to the isolation of the novel phthalimidine derivatives marilines A(1) (1a), A(2) (1b), B (2), and C (3). The absolute configurations of the enantiomeric compounds 1a and 1b were assigned by a combination of experimental circular dichroism (CD) investigations and quantum chemical CD calculations. The skeleton of marilines is most unusual, and its biosynthesis is suggested to require uncommon biochemical reactions in fungal secondary metabolism. Both enantiomers, marilines A(1) (1a) and A(2) (1b), inhibited human leukocyte elastase (HLE) with an IC(50) value of 0.86 μM.

The marine-derived fungus Stachylidium sp. was isolated from the sponge Callyspongia cf. C. flammea. Four new, putatively tyrosine-derived and O-prenylated natural products, stachylines A -D (1 -4), were obtained from the fungal extract. The structures of 1 -4 were elucidated based on extensive spectroscopic analyses. The absolute configuration of compound 2 was established by Mosher's method. Stachyline A (1) possesses a rare terminal oxime group and occurs as an interchangeable mixture of E/Z-isomers.The marine environment harbours approximately half of the global biodiversity and is estimated to contain between 3 and 500 million different species, offering an almost infinite resource for novel compounds. 1 Among these organisms marine-derived fungi became known as prolific producers of structurally most intriguing compounds. 2 In general, tyrosine derivatives have only rarely been reported from fungi, and in most cases such compounds were obtained from strains originating from environmentally extreme habitats, e.g. tyrosol carbamate which was isolated from the deep-water fungus Arthrinium sp. 3 Phytomyces sp., producing O-prenylated tyrosine derivatives, is an extremophile collected from an acid mine waste rich in toxic metals. 4 Another unusual case is aspergillusol A, an α-glucosidase inhibitor obtained from the sponge-derived fungus Aspergillus aculeatus which is reported to be the only known fungal tyrosine derivative to possess an oxime group. 5 Secondary metabolites with an oxime substituent are rare, and most of the reported examples have potent bioactivity, e.g. the actinomycete-derived nocardicins displayed strong antibiotic activity, 6 and brevioxime from Penicillium brevicompactum inhibited the biosynthesis of insect juvenile hormones. 7 P. olsonii produced 2-(4-hydroxyphenyl)-2-oxoacetaldehyde oxime (PHBA) which regenerated phosphorylated cholinesterase. 8 The oxime geometrical isomers collismycins A and B were isolated from Streptomyces sp. MQ22 which inhibited dexamethasone glucocorticoid receptor binding. 9During our search for new cytotoxic natural products an extract of the marine-derived fungus Stachylidium sp. was found to be active. During chromatographic separations it became clear that this fungus produces a vast array of secondary metabolites with intriguing structural features, among them the four novel, putatively tyrosine-derived and O-prenylated natural products, stachylines A -D (1 -4). Stachyline A (1) is distinguished by an oxime terminal group, probably derived through biosynthetic reactions similar to those known for cyanogenic glycosides and nocardicin A formation. [10][11][12][13][14] The molecules were evaluated in a number of biological assays, to date however no considerable activity was detected.* To whom correspondence should be addressed. Results and DiscussionThe RP-18 HPLC chromatogram of 1 contained two peaks (ratio 1:1), which when reinjected after their individual isolation, again resulted in the same chromatogram. This result suggested that compound 1 exi...

The myxobacterial strain Nannocystis pusilla B150 synthesizes the structurally new polyketides phenylnannolone A–C. Apart from some common volatiles and siderophores, these are the first natural products from the genus Nannocystis. Phenylnannolone A shows inhibitory activity towards the ABCB1 gene product P‐glycoprotein and reverses daunorubicin resistance in cancer cells. To decipher the biochemical reactions leading to the formation of phenylnannolone A, the putative biosynthetic genes were identified (phn1, phn2). Phn2 is a polyketide synthase (PKS) with an NRPS‐like loading module, and its domain order is consistent with the phenylnannolone A structure. The functionality and substrate selectivity of the loading module were determined by means of a γ‐18O4‐ATP pyrophosphate exchange and a phosphopantetheine ejection assay. A specific activation of cinnamic acid by the AMP‐ligase was detected. Phn1 is a putative butyryl‐CoA carboxylase (BCC), providing ethylmalonyl‐CoA for the formation of the ethyl‐substituted part of phenylnannolone A. Phn1 is the first BCC found in biosynthetic genes for an ethyl‐substituted natural compound. Biosynthesis of phenylnannolone A, putatively encoded by phn1 and phn2, thus utilizes the first biosynthetic machinery in which both a BCC and a PKS are involved.