Anja Krick

In vitro chemopreventive potential of fucophlorethols from the brown alga Fucus vesiculosus L. by anti-oxidant activity and inhibition of selected cytochrome P450 enzymes.

Within a project focusing on the chemopreventive potential of algal phenols, two phloroglucinol derivatives, belonging to the class of fucophlorethols, and the known fucotriphlorethol A were obtained from the ethanolic extract of the brown alga Fucus vesiculosus L. The compounds trifucodiphlorethol A and trifucotriphlorethol A are composed of six and seven units of phloroglucinol, respectively. The compounds were examined for their cancer chemopreventive potential, in comparison with the monomer phloroglucinol. Trifucodiphlorethol A, trifucotriphlorethol A as well as fucotriphlorethol A were identified as strong radical scavengers, with IC(50) values for scavenging of 1,1-diphenyl-2 picrylhydrazyl radicals (DPPH) in the range of 10.0-14.4 microg/ml. All three compounds potently scavenged peroxyl radicals in the oxygen radical absorbance capacity (ORAC) assay. In addition, the compounds were shown to inhibit cytochrome P450 1A activity with IC(50) values in the range of 17.9-33 microg/ml, and aromatase (Cyp19) activity with IC(50) values in the range of 1.2-5.6 microg/ml.

Antiprotozoal Activities of Heterocyclic-Substituted Xanthones from the Marine-Derived Fungus Chaetomium sp.

Investigations of the marine-derived fungus Chaetomium sp. led to the isolation of the new natural products chaetoxanthones A, B, and C (1-3). Compounds 1 and 2 are substituted with a dioxane/tetrahydropyran moiety rarely found in natural products. Compound 3 was identified as a chlorinated xanthone substituted with a tetrahydropyran ring. The configurational analysis of these compounds employed CD spectroscopy, modified Moshers method, and selective NOE gradient measurements. Compound 2 showed selective activity against Plasmodium falciparum with an IC50 value of 0.5 microg/mL without being cytotoxic toward cultured eukaryotic cells. Compound 3 displayed a moderate activity against Trypanosoma cruzi with an IC50 value of 1.5 microg/mL.

Epoxyphomalin A and B, Prenylated Polyketides with Potent Cytotoxicity from the Marine-Derived Fungus Phoma sp.

Chemical investigation of a strain of the marine-derived fungus Phoma sp. has led to the discovery of epoxyphomalin A (1) and B (2), two new prenylated polyketides with unusual structural features. Epoxyphomalin A (1) showed superior cytotoxicity at nanomolar concentrations toward 12 of a panel of 36 human tumor cell lines. In COMPARE analyses, the observed cytotoxic selectivity pattern of 1 did not correlate with those of reference anticancer agents with known mechanisms of action.

Monodictyochromes A and B, Dimeric Xanthone Derivatives from the Marine Algicolous Fungus Monodictys putredinis

Investigations of the marine-derived fungus Monodictys putredinis led to the isolation of two novel dimeric chromanones (1, 2) that consist of two uniquely modified xanthone-derived units. The structures were elucidated by extensive spectroscopic measurements including NOE experiments and CD analysis to deduce the configuration. The compounds (1, 2) were examined for their cancer chemopreventive potential and shown to inhibit cytochrome P450 1A activity with IC(50) values of 5.3 and 7.5 μM, respectively. In addition, both compounds displayed moderate activity as inducers of NAD(P)H:quinone reductase (QR) in cultured mouse Hepa 1c1c7 cells, with CD values (concentration required to double the specific activity of QR) of 22.1 and 24.8 μM, respectively. Compound 1 was slightly less potent than compound 2 in inhibiting aromatase activity, with IC(50) values of 24.4 and 16.5 μM.

A Marine Mesorhizobium sp. Produces Structurally Novel Long-Chain N-Acyl-l-Homoserine Lactones

ABSTRACT Our study focused on a Mesorhizobium sp. that is phylogenetically affiliated by 16S rRNA gene sequence to other marine and saline bacteria of this genus. Liquid chromatography-mass spectrometry investigations of the extract obtained from solid-phase extraction of cultures of this bacterium indicated the presence of several N-acyl homoserine lactones (AHLs), with chain lengths of C10 to C16. Chromatographic separation of the active bacterial extract yielded extraordinarily large amounts of two unprecedented acylated homoserine lactones, 5-cis-3-oxo-C12-homoserine lactone (5-cis-3-oxo-C12-HSL) (compound 1) and 5-cis-C12-HSL (compound 2). Quorum-sensing activity of compounds 1 and 2 was shown in two different biosensor systems [Escherichia coli MT102(pSB403) and Pseudomonas putida F117(pKR-C12)]. Furthermore, it was shown that both compounds can restore protease and pyoverdin production of an AHL-deficient Pseudomonas aeruginosa PAO1 lasI rhlI double mutant, suggesting that these signal molecules maybe used for intergenus signaling. In conclusion, these data indicate that the quorum-sensing activity of compounds 1 and 2 is modulated by the chain length and functional groups of the acyl moiety. Additionally, compound 1 showed antibacterial and cytotoxic activities.

Mode of action of epoxyphomalins A and B and characterization of related metabolites from the marine-derived fungus Paraconiothyrium sp.

Epoxyphomalins A (1) and B (2) are highly potent cytotoxic fungal metabolites. During the course of purifying larger quantities of 1 and 2 from Paraconiothyrium sp. fermentation extracts, three new epoxyphomalins (3-5) were isolated and characterized, showing modifications to the oxidation pattern of the cyclohexene moiety or of C-9 of the decalin system. IC(50) values for cytotoxicity against a panel of 36 human tumor cell lines were determined for all new compounds. Compound 4 was found to be cytotoxic particularly toward prostate PC3M (IC(50) = 0.72 μM) and bladder BXF 1218 L (IC(50) = 1.43 μM) cancer cell lines. In addition, inhibition of chymotrypsin-, caspase-, and trypsin-like activity of purified 20S proteasomes was determined for epoxyphomalins A (1) and B (2). The results indicate that compounds 1 and 2 exert their cytotoxic effect through potent inhibition of the 20S proteasome.

Variation of brominated indoles and terpenoids within single and different colonies of the marine bryozoan Flustra foliacea.

The variation of the brominated indole and diterpenoid content within single and different colonies of the bryozoan Flustra foliacea was investigated. The secondary metabolite profile and concentrations of individual components of F. foliacea samples were established using GC–MS. Samples from 17 different collecting sites were analyzed. The alkaloid and diterpene composition of F. foliacea varied greatly depending upon the site of collection. Investigation of F. foliacea samples from a single site (Helgoland, North Sea) over a period of time showed that the alkaloid and diterpenoid profile remained constant, however concentrations of individual components varied significantly. The alkaloid and diterpenoid composition of different segments of a single colony was found to be constant. Only small differences could be detected in the essential oil composition of different colonies and segments of single colonies of F. foliacea. Two of the F. foliacea alkaloids were found in the gastropods Hydrobia ulva and Gibbula cinerea, and one alkaloid in the common starfish Asteria rubens, all collected from the surface of the bryozoan.

Aromatic Polyketides from Marine Algicolous Fungi

The investigation of the marine-derived fungi Acremonium sp. and Nodulisporium sp. led to the isolation of the new natural products acremonisol A ( 1) and (3 R)-7-hydroxy-5-methylmellein ( 2). Both fungi are endophytes of marine algae. Compounds 1 and 2 are biosynthetically related by both being aromatic pentaketides belonging to the dihydroisocoumarins. All structures were elucidated by extensive spectroscopic measurements.

Noduliprevenone: A Novel Heterodimeric Chromanone with Cancer Chemopreventive Potential

Chemoprevention is considered a new strategy in fighting diverse types of cancer. To influence cancer development and progression, signaling pathways, for example, enzymes like cyclooxygenase-2, transcription factors like NF-kB, and several metabolic processes leading to activation or deactivation of carcinogenic agents, are envisaged as promising approaches. Cytochrome P450 (CYP) enzymes activate xenobiotics and thus contribute to the generation of potent carcinogens. Accordingly, inhibition of cytochrome P450 isoforms, such as CYP1A enzymes, which play an important role in polycyclic aromatic hydrocarbon (PAH) induced cancer forms, is advantageous for chemoprevention. In contrast, the induction of phase II enzymes inactivates carcinogens and accelerates their renal or biliar elimination, forming conjugates with polar ligands, such as glutathione, glucuronic acid, and acetic or sulfuric acid. NAD(P)H:quinone reductase (QR) contributes in detoxification by catalysing the two-electronaccepted reduction of quinones to their corresponding, lowmutagenic hydroquinones and is therefore often used as biomarker. Accordingly, the aim of cancer chemopreventive strategy can include the inhibition of phase I enzymes accompanied with an increased phase II metabolism. The fungus Nodulisporium sp. is an endophyte of a Mediterranean alga, and produces the novel polyketide noduliprevenone (1), an unprecedented structure consisting of two

Cytotoxic bastadin 24 from the Australian sponge Ianthella quadrangulata.

A new cytotoxic bastadin, bastadin 24 ( 1), and the previously reported bastadins 4, 5, 6, 7, 12, 13, and 21 ( 2- 8) were isolated from a polar extract of the Australian marine sponge Ianthella quadrangulata. The planar structure of bastadin 24 ( 1) was elucidated as the 25-hydroxy derivative of bastadin 6 ( 4) by employing spectroscopic techniques (NMR, MS, UV, and IR). All isolated bastadins were evaluated for their cytotoxicity toward a panel of 36 human tumor cell lines and were found to be moderately cytotoxic. Bastadin 24 ( 1) exhibited selective cytotoxic activity toward five of the 36 investigated tumor cell lines. Bastadins 7 ( 5) and 12 ( 6) significantly inhibited the serum + hEGF-induced (human epithelial growth factor) tubular formation of human umbilical vein endothelial cells (HUVEC) at a concentration of 1 mug/mL.