Chemical constituents from Gouania longipetala and Glyphaea brevis.

Five compounds were isolated altogether from the two medicinal plants. Glycerol monotricosanoate (1), palmarumycin BG1 (2) and de-O-methyllasiodiplodin (3) were isolated from Gouania longipetala. In addition, epicatechin (4) and its dimer procyanidin B2 (5) were isolated from the stem bark of Glyphaea brevis. Their structures were elucidated by using spectroscopic experiments. They exhibited radical scavenging and moderate antibacterial effects.

Scyptolin A and B, cyclic depsipeptides from axenic cultures of Scytonema hofmanni PCC 7110.

Two novel cyclic depsipeptides were isolated from axenic cultures of the terrestrial cyanobacterium Scytonema hofmanni PCC 7110 and designated scyptolin A and B. Amino acid analyses in context with mass and 1H/13C NMR spectroscopies revealed a composition typical for heterologous cyanopeptolins but containing the uncommon residue 3'-chloro-N-methyl-Tyr (cmTyr) and a unique sidechain. Scyptolin A and B both consist of the N-acylated peptide But(1)-Ala(2)-Thr(3)-Thr(4)-Leu(5)-Ahp(6) (3-amino-6-hydroxy-2-oxo-1-piperidine)-Thr(7)-cmTyr(8)-Val(9), which forms a 19-membered ring by esterification of the carboxyl of Val(9) with the hydroxyl of Thr(4). In scyptolin B, the hydroxyl of the Thr(3) residue is additionally esterified with N-butyroyl-Ala. Both scyptolin A and B exhibit selective inhibition of porcine pancreatic elastase in vitro with IC(50) values of 3.1 microg/ml.

Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110. II. Structure elucidation, stereochemistry and physico-chemical properties.

A novel class of macrolides, the sanglifehrins, was discovered by screening of actinomycete strains with a cyclophilin-binding assay. The chemical structures and absolute stereochemistries of the sanglifehrins A, B, C and D were determined unambiguously by NMR-techniques and by X-ray crystallography of the complex with cyclophilin A. Sanglifehrin A consists of a 22-membered macrocycle containing a tripeptide subunit and features in position 23 a chain of nine carbon atoms bearing a spirocyclic substituent. Sanglifehrins A and B are genuine metabolites whereas sanglifehrins C and D are artefacts.

Isolation and synthesis of a novel immunosuppressive 17alpha-substituted dammarane from the flour of the Palmyrah palm (Borassus flabellifer).

The novel triterpene 1 with a dammarane skeleton and a hitherto unknown 17alpha-substitution pattern has been isolated from the Palmyrah palm in low yield and prepared by synthesis in larger quantities. 1 was shown to be an extremely potent immunosuppressant in vitro (MLR; IC50 = 10 ng/ml) and in vivo (DTH; ED50 = 0.01 mg/kg p.o.). A glucocorticoid like activity is excluded.

Cymbimicin A and B, two novel cyclophilin-binding structures isolated from actinomycetes.

Two novel metabolites, cymbimicins A and B, were isolated from the culture broth of a strain of Micromonospora sp. by screening for cyclophilin binding metabolites from actinomycete strains. Cymbimicin A binds to cyclophilin A with a high affinity six fold lower than to that of cyclosporin A. The binding affinity of cymbimicin B is about 100 times lower. The taxonomy of the producing strain, fermentation, isolation, physical and biological properties and structure elucidation are described.

The 3D-structure of a natural inhibitor of cell adhesion molecule expression.

The three-dimensional structure of cyclopeptolide HUN-7293, a naturally-occurring inhibitor of cell adhesion molecule expression, has been determined from nuclear magnetic resonance data recorded in solution and from X-ray diffraction analysis of single crystals. The backbone conformation of HUN-7293 is characterized by two cis-peptide bonds in both the solution and crystalline state. Differences between the solution and crystal structure are visible for the orientation of some side chains and the strength of two transannular hydrogen bonds. Such structural information helps to provide insight into the molecular architecture of HUN-7293 on the atomic level and opens the way for structure-based modifications of this novel inhibitor of cell adhesion molecule expression.

Cyanopeptolin S, a sulfate-containing depsipeptide from a water bloom of Microcystis sp.

A new sulfated, cyclic depsipeptide, called cyanopeptolin S, from Microcystis sp. was isolated from a water bloom in the Auensee/Leipzig (Germany). The depsipeptide had a relative molecular mass of 925 and contained L-arginine, L-threonine, L-isoleucine, N-methyl-L-phenylalanine, a L-glutamic acid-delta-aldehyde ring system and a sulfated D-configurated glyceric acid as a side chain. The structure was elucidated by means of two-dimensional 1H and 13C nuclear magnetic resonance spectroscopy, fast atom bombardment mass spectroscopy. Fourier transformed infrared spectroscopy and combined gas-liquid chromatography/mass spectrometry. Cyanopeptolin S inhibited trypsin with an IC50 < or = 0.2 micrograms ml-1.

Pharmacological modulation of endothelial cell-associated adhesion molecule expression: implications for future treatment of dermatological diseases.

Skin diseases with an inflammatory component, regardless of their etiology, are characterized at some point by the extravasation and subsequent infiltration of leukocytes into the dermal and/or epidermal compartments. This trafficking pattern is determined by a complex series of events whereby the leukocytes interact with cell adhesion molecules (CAM), particularly those induced on endothelial cells following activation with various inflammatory mediators. Vascular CAMs belonging to the selectin family (i.e., P-selectin and E-selectin) are thought to mediate early and reversible events involving leukocyte rolling and margination along the lumenal surface of microvascular cells (post-capillary venules). Certain members of the immunoglobulin supergene family (i.e., VCAM-1 and ICAM-1) regulate later and irreversible steps which lead to firm attachment and subsequent diapedesis of leukocytes. Accumulating evidence suggests that if one blocks the ligand-binding sites between leukocytes and endothelial cells, or inhibits vascular CAM expression, hematopoietic cell extravasation and progressive inflammatory events can be greatly diminished. To identify such inhibitors we developed a cell-based Elisa using the human microvascular cell line HMEC-1. As reported in the present paper, this approach yielded a naturally-occurring, low molecular weight compound which potently inhibits cytokine-induced adhesion molecule expression on cultured endothelial cells, without modulating "house-keeping" proteins.

The discovery of capsazepine, the first competitive antagonist of the sensory neuron excitants capsaicin and resiniferatoxin.

Capsaicin and resiniferatoxin are natural products which act specifically on a subset of primary afferent sensory neurons to open a novel cation-selective ion channel in the plasma membrane. These sensory neurons are involved in nociception, and so, these agents are targets for the design of a novel class of analgesics. Although synthetic agonists at the capsaicin receptor have been described previously, competitive antagonists at this receptor would be interesting and novel pharmacological agents. Structure-activity relationships for capsaicin agonists have previously been rationalized, by ourselves and others, by dividing the capsaicin molecule into three regions--the A (aromatic ring)-, B (amide bond)-, and C (hydrophobic side chain)-regions. In this study, the effects on biological activity of conformational constraint of the A-region with respect to the B-region are discussed. Conformational constraint was achieved by the introduction of saturated ring systems of different sizes. The resulting compounds provided agonists of comparable potency to unconstrained analogues as well as a moderately potent antagonist, capsazepine. This compound is the first competitive antagonist of capsaicin and resiniferatoxin to be described and is active in various systems, in vitro and in vivo. It has recently attracted considerable interest as a tool for dissecting the mechanisms by which capsaicin analogues evoke their effects. NMR spectroscopy and X-ray crystallography experiments, as well as molecular modeling techniques, were used to study the conformational behavior of a representative constrained agonist and antagonist. The conformation of the saturated ring contraint in the two cases was found to differ markedly, dramatically affecting the relative disposition of the A-ring and B-region pharmacophores. In agonist structures, the A- and B-regions were virtually coplanar in contrast to those in the antagonist, in which they were approximately orthogonal. A rationale for agonist and antagonist activity at the capsaicin receptor is proposed, based on the consideration of these conformational differences.

Cyanopeptolins, new depsipeptides from the cyanobacterium Microcystis sp. PCC 7806.

Four depsipeptides (peptide lactones), called cyanopeptolins A, B, C and D, have been isolated from the cyanobacterium Microcystis sp. PCC 7806. They possess identical structures consisting of cyclic L-glutamic acid-gamma-aldehyde, L-leucine, N-methyl-phenylalanine, L-valine, L-threonine, L-aspartic acid, hexanoic acid and a variable basic amino acid. This variable amino acid can be L-arginine (cyanopeptolin A), L-lysine (cyanopeptolin B), N epsilon-methyl-L-lysine (cyanopeptolin C) and N epsilon,N epsilon-dimethyl-L-lysine (cyanopeptolin D), respectively. The L-glutamic acid-gamma-aldehyde and the amino group of L-leucine form an unusual 3-amino-6-hydroxy-2-oxo-1-piperidine system. L-Threonine is connected to L-valine via its hydroxy-group forming an ester bonding. The hexanoic acid residue is attached to the N-terminal aspartic acid residue which is not a part of the ring structure. The isolation procedure of the four cyanopeptolins as well as structure elucidation are described. Amino acid analysis, GC/MS analysis, FAB-MS and several NMR techniques were used to reveal the structures.