Clinical trial update and novel therapeutic approaches for metastatic prostate cancer.

Recurrent prostate cancer (PCa) remains a major clinical challenge. Invasive and metastatic PCa lesions often exhibit a partial and time-limited response to therapy before the cancer progresses and the patient succumbs to the disease. Despite recent advances in early diagnosis and treatment, approximately one-third of treated patients will relapse and become resistant to currently available treatments. In this review we evaluate current treatment practices and recent advances in therapy for localized prostate malignancy and advanced, metastatic prostate cancer. Some of the promising new drugs for PCa treatment include MDV3100, an androgen receptor (AR) antagonist that prevents androgens from binding to the AR and nuclear translocation and co-activator recruitment of the ligand-receptor complex; abiraterone, an orally administered drug that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis, CYP17; and several newer cytotoxic drugs (epothilones, satraplatin). Key new insights are that cancer stem cells play a role in PCa and that PCa cells are dependent on the AR for proliferation, even in the hormone refractory state of the disease. We also discuss potential molecular targets for new drug candidates for the treatment of metastatic PCa.

Laschiatrion, a new antifungal agent from a Favolaschia species (Basidiomycetes) active against human pathogens.

Laschiatrion (1), a new antifungal antibiotic, was isolated from fermentations of Favolaschia sp. 87129. (1) exhibits broad in vitro activity against several human pathogens while no antibacterial and cytotoxic activities could be detected. The structure was elucidated by spectroscopic techniques. As to our knowledge laschiatrion possesses a new steroid skeleton.

Characteristics, clinical effect profile and tolerability of a nasal spray preparation of Artemisia abrotanum L. for allergic rhinitis.

A nasal spray formulation containing an extract of Artemisia abrotanum L. was developed for therapeutic use in patients with allergic rhinitis and other upper airway disorders. The nasal spray preparation used contains a mixture of essential oils (4 mg/ml) and flavonols (2.5 microg/ml), of which some components have been shown to possess antiinflammatory, expectorant, spasmolytic as well as antiseptic and antimicrobial activities. The most important constituents in the essential oil fraction of the preparation are 1,8-cineole, linalool and davanone, while the flavonol fraction contains centauredin, casticin and quercetin dimethyl-ethers. No trace of thujon was observed in the essential oil of the Artemisia abrotanum L. genotype "Tycho" used for the manufacture of the nasal spray preparation. In 12 patients with diagnoses of allergic rhinitis, allergic conjunctivitis and/or bronchial obstructive disease, the nasal spray was given immediately after the appearance of characteristic allergic nasal symptoms. In 10 of the 12 patients, allergic rhinitis with nasal congestion, sneezing and rhinorrhea was dominant. After administration of the nasal spray, all patients experienced a rapid and significant symptom relief of nasal symptoms, comparable to the effect of antihistamine and chromoglicate preparations which several of the patients had used previously. The effect was present within 5 minutes after the administration and lasted for several hours. In 7 of the 10 rhinitis patients with concomitant symptoms of allergic conjunctivitis, a significant subjective relief of eye symptoms was also experienced. In 3 of the 6 patients who had a history of characteristic symptoms of endogenous, exogenous or exercise induced bronchial obstructive disease, there was a bronchial symptom relief by the nasal spray preparation which was experienced as rapid and clinically significant. It is concluded from the present proof of concept study, that a nasal spray formulation containing an extract characterised by a mixture of essential oils and flavonols from the Artemisia abrotanum L. genotype "Tycho", appears to be clinically useful and suitable for the prophylactic and therapeutic management of patients with allergic rhinitis and adjuvant symptoms.

Reactivity of contact allergenic haptens to amino acid residues in a model carrier peptide, and characterization of formed peptide-hapten adducts.

The type of chemical reaction between hapten and carrier protein in the formation of a complete antigen in vivo giving rise to an allergic contact dermatitis (ACD, type IV allergy) is essentially unknown. About 4000 low-molecular organic compounds are known to have allergenic properties. alpha,beta-Unsaturated carbonyl structures are frequently present among these compounds. Haptens giving rise to antibody formation and type I allergy have been shown to add predominantly to lysine in the carrier protein. In this paper, the reactivity of activated type IV haptens to a model peptide is reported. Essentially all amino acids with nucleophilic properties were present in the model peptide. Investigation of the relative reactivities of the amino acid residues to activated haptens under biomimetic conditions is performed in order to determine the proportions between the adducts of the different amino acid moieties. In all cases, the electrophilic alpha,beta-unsaturated haptens were found to be added to the cysteine residue and no lysine adduct was recorded. Nuclear magnetic resonance (NMR) spectroscopy was used to exclude steric hindrance of any amino acid residue in the addition reaction. The hapten-modified peptides were isolated and characterized by NMR and mass spectrometry.

Synthesis of (+)-galiellalactone. Absolute configuration of galiellalactone.

[reaction: see text]. (+)-Galiellalactone was synthesized starting from (R)-(+)-pulegone. Natural and synthetic galiellalactone have opposite optical rotations, demonstrating that the structure of the natural product is 1a.

Unnatural natural products from the transannular cyclization of lathyrane diterpenes.

The potential of macrocyclic diterpenoids to afford natural product-like polycyclic compounds was demonstrated by the conversion of two lathyrane Euphorbia factors into a series of densely functionalized diterpenoids of unnatural skeletal type. Apparently, Nature is far from having fully exploited the built-in reactivity of these compounds to generate chemical diversity.

Collinone, a new recombinant angular polyketide antibiotic made by an engineered Streptomyces strain.

Large chromosomal DNA fragments containing different parts of the putative rubromycin polyketide synthase gene cluster were cloned and functionally expressed in S. coelicolor CH999. Expression of these clones yielded 5 approximately 10 metabolites that were not detected in S. collinus culture extracts. This paper focusses on one of the new metabolites, termed collinone, that was isolated in large quantities and purified for spectroscopic structure determination and biological screening assays. Collinone is a heavily oxidized angular hexacyclic compound containing an unusual 1,4,5,8(2H,3H)-anthracenetetrone moiety previously only reported to be present in antibiotics SF2446A1, A2, A3, B1 and B2 isolated from Streptomyces sp. SF2446. Structure analysis of collinone indicates a tridecaketide with a 26 carbon backbone. The basic benz[a]naphthacene ring system of collinone is angular, similar to the aglycones of the well-known angucycline and angucyclinone antibiotics. While collinone showed antibacterial activity against vancomycin-resistant enterococci, no antifungal or significant antiviral activities were detected. Collinone could be a good starting point to obtain new bioactive angucyclin(on)e-like compounds by further genetic engineering of its pathway.

Mariannaepyrone--a new inhibitor of thromboxane A2 induced platelet aggregation.

Mariannaeapyrone ((E)-2-(1,3,5,7-tetramethyl-5-nonenyl)-3,5-dimethyl-6-hydroxy-4H-pyran-4-one) is a new fungal metabolite isolated from fermentations of the common mycophilic deuteromycete Mariannaea elegans. The chemical structure of the 4-pyrone was determined by spectroscopic techniques. Mariannaeapyrone is a selective inhibitor of the thromboxane A2 induced aggregation of human platelets, whereas only weak cytotoxic and antimicrobial effects could be observed.

Coprinol, a new antibiotic cuparane from a Coprinus species.

Coprinol, a new antibacterial cuparane, was isolated from fermentations of a Coprinus sp. Its biological activities were investigated and its structure was elucidated by spectroscopic methods. The new antibiotic exhibited activitiy against multidrug-resistant Gram-positive bacteria in vitro. Two derivatives were synthesized and their activities compared to the parent compound.

Oxygenated sesquiterpenoids from a nonpoisonous sardinian chemotype of giant fennel (Ferula communis).

The roots of the nonpoisonous chemotype of giant fennel (Ferula communis) from Sardinia afforded a novel cadinanetriol (1), whose structure was established by spectroscopic data and confirmed by synthesis from the E,E-Delta (1(10),5) germacradiene allohedycariol. A number of known compounds were also identified. Despite the lack of morphological differences, a broad chemical diversity exists within giant fennel, underlying the contrasting data on its poisonous properties.

Heterologous expression of the naphthocyclinone hydroxylase gene from Streptomyces arenae for production of novel hybrid polyketides.

Streptomyces arenae produces at least four different isochromanequinone antibiotics, the naphthocyclinones, of which the beta- and gamma-form are active against Gram-positive bacteria. The naphthocyclinone biosynthesis gene cluster was isolated from Streptomyces arenae DSM 40737 and by sequence analysis the minimal polyketide synthase genes and several genes encoding tailoring enzymes were identified. Southern blot analysis of the naphthocyclinone gene cluster indicated that a 3.5 kb BamHI fragment located approximately 9 kb downstream of the minimal PKS genes hybridizes to the schC hydroxylase DNA probe isolated from S. halstedii. Two complete and one incomplete open reading frames were identified on this fragment. Sequence analysis revealed strong homology to the genes of the actVA region of S. coelicolor, to several (suggested) hydroxylases and a putative FMN-dependent monooxygenase. The proposed hydroxylase, encoded by ncnH, could hydroxylate aloesaponarin II, a molecule that is produced by the actinorhodin minimal polyketide synthase in combination with the actinorhodin ketoreductase, aromatase and cyclase. Furthermore, this enzyme is capable of accepting additional polyketide core structures that contain a 5-hydroxy-1,4-naphthoquinone moiety as substrates which makes it an interesting tailoring enzyme for the modification of polyketide structures.

Diarylheptanoids from Myrica arborea.

Investigations of the stem and root bark of Myrica arborea (Myricaceae) have yielded two novel diarylheptanoids, myricarborin and 11-O-beta-D-xylopyranosylmyricanol along with the known myricanol and 5-O-beta-D-glucopyranosylmyricanol. The structures of the novel compounds were determined by spectroscopic methods.

Bioactive sesquiterpenes from the basidiomycete Resupinatus leightonii.

1(10),4-Germacradiene-2,6,12-triol (1), a new germacrane sesquiterpene, and 1,6-farnesadiene-3,10,11-triol (2), a known nerolidol derivative, were isolated from submerged cultures of the basidiomycete Resupinatus leightonii. Both compounds inhibited cAMP-induced appressorium formation in Magnaporthe grisea and showed cytotoxic activity. The structure of 1 was determined by NMR and mass spectroscopic methods.

New variotin analogues from Aspergillus viridi-nutans.

Besides the antifungal agents variotin (1), wasabidienone B(0) (4), and phomaligin A (5), two new but inactive metabolites, viriditin (2) and O-methylviriditin (3), were isolated from extracts of the culture filtrate of liquid cultures of a strain of Aspergillus viridi-nutans. In addition, wasabidienone B(1) (6) was isolated and characterized by spectroscopy.

Secondary metabolites from a Gloeophyllum species.

Six new sesquiterpenoids, four rearranged illudalanes, one rearranged protoilludane and one sterpurane, were isolated from fermentations of Gloeophyllum sp. 97022. Their structures were elucidated by spectroscopy. Gloeophyllol B and C show weak antifungal activity, while 1-hydroxy-3-sterpurene shows weak antifungal, antibacterial and cytotoxic activities.

2-Oxo-2H-Pyrimido[2,1-b]benzothiazoles inhibit brain benzodiazepine receptor binding in vitro.

2-Oxo-2H-pyrimido[2,1-b]benzothiazole derivatives were found to inhibit the in vitro binding of (3)H-Ro 15-1788 ((3)H-flumazenil) to rat cortical benzodiazepine receptors with IC(50) values in the range of 0.7-13 micromol/l. The most potent compound, 2-oxo-4-phenyl-2H-pyrimido[2,1-b]- benzothiazole showed a similar potency to inhibit (3)H-Ro 15-1788 binding to membrane preparations of rat brain cortex, cerebellum and hippocampus as well as to various subunit combinations of recombinant human gamma-aminobutyric acid(A)/benzodiazepine receptors. Scatchard plot analysis showed that 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole is a competitive inhibitor of (3)H-Ro 15-1788 binding to rat brain cortical membrane preparations.

Tyrosinase-mediated formation of a reactive quinone from the depigmenting agents, 4-tert-butylphenol and 4-tert-butylcatechol.

Exposure of the skin to certain phenols or catechols such as 4-tert-butylphenol (TBP) and 4-tert-butylcatechol (TBC) may cause leukoderma. These substances are used in the polymer industry and numerous cases have been reported. Several theories of the mechanism for chemical leukoderma have been suggested. In the present study, TBP and TBC are shown to be oxidised by tyrosinase. The oxidation of TBC yields a quinone that is further investigated on its reactions with cysteine or glutathione (GSH). The products formed are isolated and identified by mass spectrometry and nuclear magnetic resonance as being 4-tert-butyl-6-S-cysteinylcatechol (cys-TBC) and 4-tert-butyl-6-S-glutathionylcatechol (GS-TBC). The reactive quinone is a strongly electrophilic substance that rapidly reacts with GSH. A depletion of the GSH defence system may give conditions where the quinone lives long enough to effect its toxic properties. The influence of the reactive tert-butylquinone on enzymatic activities is demonstrated by the inhibition of glyceraldehyde-3-phosphate dehydrogenase.

Neobulgarones A approximately F from cultures of Neobulgaria pura, new inhibitors of appressorium formation of Magnaporthe grisea.

Six new dimeric anthraquinone derivatives, neobulgarones A (3a), B (3b), C (4a), D (4b), E (5a) and F (5b), were isolated from the mycelia of the ascomycete Neobulgaria pura together with the monomeric carviolin (1) and 1-O-methylemodin (2). All new compounds inhibited the formation of appressoria in germinating conidia of Magnaporthe grisea on inductive (hydrophobic) surface. The compounds exhibited moderate cytotoxic, but no antifungal, antibacterial, or phytotoxic activities.

The irpexans, a new group of biologically active metabolites produced by the basidiomycete Irpex sp. 93028.

Five novel antibiotics described as irpexans (1, 2, 3a, 3b, 4) were isolated from fermentations of an Irpex species in the course of a screening for new inhibitors of AP-1 and NF-kappaB mediated signal transduction pathways in COS-7 cells using secreted alkaline phosphatase (SEAP) as a reporter gene. The expression of an AP-1 and NF-kappaB driven SEAP reporter gene was inhibited in a dose dependent manner with 14-acetoxy-15-hydroxyirpexan (3b) being the most potent compound, followed by 14,15-irpexanoxide (2), 14,15-dihydroxyirpexan (3a) and 14-acetoxy-22,23-dihydro-15,23-dihydroxyirpexan (4). Irpexan (1) exhibited no activity. The irpexans (1, 2, 3a, 3b, 4) are characterized by weak cytotoxic but neither antibacterial nor antifungal activities. All five compounds are terpenoids with a mannose moiety. The structures were elucidated by spectroscopic methods.