Band 72, Heft 1-2

Echinocandins are an important group of cyclic non-ribosomal peptides with strong antifungal activity produced by filamentous fungi from Aspergillaceae and Leotiomycetes. Their structure is characterized by numerous hydroxylated non-proteinogenic amino acids. Biosynthetic clusters discovered in the last years contain up to six oxygenases, all of which are involved in amino acid modifications. Especially, variations in the oxidation pattern induced by these enzymes account for a remarkable structural diversity among the echinocandins. This review provides an overview of the current knowledge of echinocandin biosynthesis with a special focus on diversity-inducing oxidation steps. The emergence of metabolic diversity is further discussed on the basis of a comprehensive overview of the structurally characterized echinocandins, their producer strains and biosynthetic clusters. For the pneumocandins, echinocandins produced by Glarea lozoyensis , the formation of metabolic diversity in a single organism is analyzed. It is compared to two common models for the evolution of secondary metabolism: the ‘target-based’ approach and the ‘diversity-based’ model. Whereas the early phase of pneumocandin biosynthesis supports the target-based model, the diversity-inducing late steps and most oxidation reactions best fit the diversity-based approach. Moreover, two types of diversity-inducing steps can be distinguished. Although incomplete hydroxylation is a common phenomenon in echinocandin production and secondary metabolite biosynthesis in general, the incorporation of diverse hydroxyprolines at position 6 is apparently a unique feature of pneumocandin biosynthesis, which stands in stark contrast to the strict selectivity found in echinocandin biosynthesis by Aspergillaceae. The example of echinocandin biosynthesis shows that the existing models for the evolution of secondary metabolism can be well applied to parts of the pathway; however, thus far, there is no comprehensive theory that could explain the entire biosynthesis.

An indole alkaloid, 2-(5-hydroxy-1 H -indol-3-yl)-2-oxo-acetic acid ( 1 ) isolated for the first time from nature, in addition to the nine known compounds 5-hydroxy-1 H -indole-3-carboxylic acid methyl ester ( 2 ), alocasin B ( 3 ), hyrtiosin B ( 4 ), α-monopalmitin ( 5 ), 1- O - β -D-glucopyranosyl-(2 S , 3 R , 4 E , 8 Z )-2-[(2( R )-hydroctadecanoyl) amido]-4,8-octadecadiene-1,3-diol ( 6 ), 3- epi -betulinic acid ( 7 ), 3- epi -ursolic acid ( 8 ), β -sitosterol ( 9 ) and β -sitosterol 3- O - β -D-glucoside ( 10 ) were isolated from the rhizomes of Alocasia macrorrhiza (Araceae). Their structures were elucidated by 1D and 2D NMR spectroscopic data. Of these compounds, 6 exhibited the strongest cytotoxicity against the four tested human cancer cell lines (IC 50 of about 10 µM against Hep-2 larynx cancer cells).

A new C-30 steroid, 3β-,5α-,6β-,11α-,20β-pentahydroxygorgosterol ( 1 ), and a new diterpenoid, xeniumbellal ( 2 ), along with three known aromadendrane-type sesquiterpenes, aromadendrene ( 3 ), palustrol ( 4 ) and viridiflorol ( 5 ), were isolated from the soft coral Xenia umbellata . Chemical structures were determined by analyzing their NMR and MS data. The antimicrobial and antitumor activities of the isolated compounds were examined. Both 1 and 2 showed moderate antibacterial activities, especially against the multidrug-resistant Acinetobacter baumannii (MIC 0.22 and 0.28 mM, respectively); while 2 showed antitumor activity against a lymphoma cell line with LD 50 0.57 mM and was nontoxic to Artemia salina at all tested concentrations up to about 4 mM.

A comparative investigation of hydro-distilled essential oils from aerial parts of Mentha longifolia L. (ML), Mentha microphylla K.Koch (MM), Mentha australis R.Br. (MA), and Teucrium polium L. (TP) growing in Al Madinah Al Munawwarah, Saudi Arabia, was carried out. The total numbers of identified constituents were 22, 23, 14, and 20 in ML, MM, MA, and TP oils, representing 93.0, 99.3, 78.1, and 81.1% of the total oil composition, respectively. Pulegone (40.7%) and cineole (33.4%) were the major components in ML, whereas carvone (64.6%) was the major one in MM. Furthermore, β-linalool (22.9%) and α-terpineol (12%) were the major components in MA, whereas, ( E )-3-caren-2-ol accounted for 12.1% in TP. The essential oils of TP and MA exhibited promising activities against Leishmania donovani promastigotes with IC 50 values of 2.3 and 3.7 μg/mL, respectively. In contrast, MA essential oils exhibited antifungal activities towards Candida krusei and C. glabrata with IC 50 values of 1 and 1.2 μg/mL, respectively.

Amphidinol 3 (AM3) and theonellamide A (TNM-A) are potent antifungal compounds produced by the dinoflagellate Amphidinium klebsii and the sponge Theonella spp. , respectively. Both of these metabolites have been demonstrated to interact with membrane lipids ultimately resulting in a compromised bilayer integrity. In this report, the activity of AM3 and TNM-A in ternary lipid mixtures composed of 1-palmitoyl-2-oleoyl- sn -glycerol-3-phosphocholine (POPC):brain sphingomyelin:cholesterol at a mole ratio of 1:1:1 or 3:1:1 exhibiting lipid rafts coexistence is presented. It was found that AM3 has a more extensive membrane permeabilizing activity compared with TNM-A in these membrane mimics, which was almost complete at 15 μM. The extent of their activity nevertheless is similar to the previously reported binary system of POPC and cholesterol, suggesting that phase separation has neither beneficial nor detrimental effects in their ability to disrupt the lipid bilayer.

Herpes simplex virus type-1 (HSV-1) is a member of alpha-herpesviridae family and is known to cause contagious human infections. The marine habitat is a rich source of structurally unique bioactive secondary metabolites. A small library of marine natural product classes 1–10 has been screened to discover a new hit entity active against HSV-1. Manzamine A showed potent activity against HSV-1 via targeting the viral gene ICP0. Manzamine A is a β-carboline alkaloid isolated from the Indo-Pacific sponge Acanthostrongylophora species. Currently, acyclovir is the drug of choice for HSV-1 infections. Compared with 50 µM acyclovir, manzamine A at 1 µM concentration produced potent repressive effects on viral replication and release of infectious viruses in SIRC cells in recent studies. The potent anti-HSV-1 activity of manzamine A prompted a preliminary structure-activity relationship study by testing targeted manzamines. These included 8-hydroxymanzamine A ( 11 ), to test the effect of the C-8 hydroxy substitution at the β-carboline moiety; manzamine E ( 12 ), to assess the importance of substitution at the azacyclooctane ring; and ircinal A ( 13 ), to determine whether the β-carboline ring is required for the activity. Manzamine A was chemically transformed to its salt forms, manzamine A monohydrochloride ( 14 ) and manzamine A monotartrate ( 15 ), to test whether improving water solubility and hydrophilicity will positively affect the activity. Compounds were tested for activity against HSV-1 using fluorescent microscopy and plaque assay. The results showed the reduced anti-HSV-1 activity of 11 , suggesting that C-8 hydroxy substitution might adversely affect the activity. Similarly, manzamines 12 and 13 showed no activity against HSV-1, indicating the preference of the unsubstituted azacylcooctane and β-carboline rings to the activity. Anti-HSV-1 activity was significantly improved for the manzamine A salts 14 and 15 , suggesting that improving the overall water solubility as salt forms can significantly enhance the activity. Manzamines have significant potential for future development as anti-HSV-1 entity.

The phytochemical study of Stereocaulon montagneanum harvested in Sumatra (Indonesia) led to the isolation of 11 known compounds including two metabolites not previously described in the genus Stereocaulon , peristictic acid ( 8 ) and menegazziaic acid ( 10 ). The complete 1 H and 13 C NMR spectral assignments of stictic acid derivatives are reported with some revisions. Five depsidones belonging to the stictic acid chemosyndrome were superoxide anion scavengers as potent as ascorbic acid and with no toxicity on two human cell lines.

This work was aimed at a progressive formulation of drugs into chitosan hydrogels. It was taken into consideration that a therapeutic effect of the drugs could be enhanced by a combination of natural compounds with chemical (synthetic) drugs. In this work, sage essential oil (SEO) bicyclic monoterpenes with antiflogistic, antiseptic, and antimycotic properties were combined with terbinafine (TB) having a strong antimycotic activity. Detail optimization of the hydrogel-drugs composition (SEO monoterpenes, TB, chitosan, and polysorbate 80 concentrations), based on permeation experiment and UV absorption/GC-MS analysis of permeated species (eucalyptol, camphor, borneol, thujone, TB) in dialysates, was made. Concerning the active drugs formulation, an optimum concentration of TB was set at the level providing maximum release of the SEO monoterpenes. In vitro activity of the dialysates from the optimized hydrogel was tested against Candida albicans showing that a minimum inhibition concentration was significantly exceeded. The experimental results revealed that the chitosan hydrogel was suitable for the simultaneous formulation of the natural drugs (SEO) with chemical drug (TB) resulting in the preparation with acceptable stability, required gel properties, and significant biological activity. Such preparation should be effective in an antimycotic dermal use.

The leaves of Campylospermum elongatum have furnished the cyano-glycoside (lithospermoside), nine isomeric biflavonoid derivatives among which five are I 3 –II 6 linked (robustaflavone; 4′- O -methyl robustaflavone; 4′,4″′-di- O -methyl robustaflavone; 7,4′,4″-tri- O -methyl robustaflavone; 4′,7″-di- O -methyl robustaflavone) and four I 3 –II 8 linked (amentoflavone; 7- O -methyl amentoflavone; 7,7″-di- O -methyl amentoflavone; 7, 4′,7″-tri- O -methyl amentoflavone) and a flavone glycoside, 4″- O -methyl-7- O -β- d -galactosylapigenin. All structures were established from a complete spectroscopic analysis (MS, IR, 1D, and 2D NMR, including HSQC, HMBC, and NOESY) as well as by comparing the obtained spectroscopic data with literature. This is the first report on the characterization of 4′- O -methyl-7- O -β- d -galactosylapigenin from the genus campylospermum and thus has important chemotaxonomic implications.