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.

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.

Anti-lymphoproliferative activity of brown adipose tissue of hibernating ground squirrels is mainly caused by AMP.

A fraction with mol wt < 1 kDa was obtained from the brown fat of hibernating ground squirrels (Citellus undulatus) by means of delipidization, acid extraction, ultracentrifugation and ultrafiltration. This fraction suppressed the proliferation of mouse lymph node cells under standard mitogenic stimuli for T lymphocytes. In contrast, the fraction with mol wt < 1 kDa obtained from the brown fat of active ground squirrels in spring did not display such activity. Further HPLC purification of the biologically active fraction and chemical and structural analysis of its most potent antilymphoproliferative component revealed that this is adenosine 5'-monophosphate (AMP). These data lend support to the notion that in hibernating mammals AMP originating, at least partly, from the brown fat down-regulates the seasonally-dependent proliferation of the thymus.

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.

Clavamycins, new clavam antibiotics from two variants of Streptomyces hygroscopicus. II. Isolation and structures of clavamycins A, B and C from Streptomyces hygroscopicus NRRL 15846, and of clavamycins D, E and F from Streptomyces hygroscopicus NRRL 15879.

Clavamycins A, B, C, D, E and F represent new members of the clavam antibiotics group. Their purification was achieved by a variety of preparative chromatographic methods, essentially on reversed phase carrier. The structures were deduced from spectroscopic properties, especially from extensive NMR studies.

Evidence for a common siderophore transport system but different siderophore receptors in Neurospora crassa.

Uptake and competition experiments were performed with Neurospora crassa and Penicillium parvum by using 14C-labeled coprogen and 55Fe-labeled ferrichrome-type siderophores. Several siderophores of the ferrichrome family, such as ferrichrome, ferricrocin, ferrichrysin, and tetraglycyl-ferrichrome as well as the semisynthetic ferricrocin derivatives O-(phenyl-carbamoyl)-ferricrocin and O-(sulfanilyl-carbamoyl)-ferricrocin were taken up by N. crassa. The ferrichrome-type siderophores used vary in the structure of the peptide backbone but possess a common lambda-cis configuration about the iron center and three identical ornithyl-delta-N-acetyl groups as surrounding residues. This suggests that these ferrichrome-type siderophores are recognized by a common ferrichrome receptor. We also concluded that the ferrichrome receptor is lambda-cis specific from the inability to take up the synthetic enantiomers, enantio-ferrichrome and enantio-ferricrocin, possessing a delta-cis configuration about the iron center. On the other hand, we found that coprogen, possessing a delta-absolute configuration and two trans-anhydromevalonic acid residues around the metal center, was also taken up by N. crassa and was competitively inhibited by the ferrichrome-type siderophores. We therefore propose the existence of a common siderophore transport system but the presence of different siderophore receptors in N. crassa. In addition, ferrirubin, which is very slowly transported by N. crassa, inhibited both coprogen and ferrichrome-type siderophore transport. Contrary to the findings with N. crassa, transport experiments with P. parvum revealed the presence of a ferrichrome receptor but the absence of a coprogen receptor; coprogen was neither transported nor did it inhibit the ferrichrome transport.

Iron supply of Escherichia coli with polymer-bound ferricrocin.

Uptake of ferric iron from ferricrocin was studied in Escherichia coli using a polymer-coupled ferricrocin that was unable to penetrate into the cell. Ferricrocinyl polyethylene glycol succinate (Mr 7000 -- 8500) promoted growth of E. coli K-12 AB2847 aroB under iron-limiting conditions. In iron-starved cells, uptake of 55Fe could be demonstrated; the amount of iron accumulated amounted to 10% of that observed with free ferricrocin. The iron supply by ferricrocin bound to polyethylene glycol was strictly dependent upon the functions expressed by the tonA and the tonB genes, as was the iron uptake promoted by free ferricrocin. Polymer-bound ferricrocin protected cells against colicin M and phage T5 by competition for the common tonA-coded outer membrane receptor protein. In addition, the rate of iron transport via the negatively charged ferricrocinyl succinate was as fast as via the neutral ferricrocin molecule. No ligand was found associated with the cells. Penetration of chelator beyond receptor is not necessary for siderophore-mediated iron uptake. It is concluded that sufficient amounts of iron can be released from the polymer complex to satisfy growth requirements.

(S)-3-p-Methoxyphenyl-3-acetylaminopropan-1-ol, a New Metabolite of an Actinomycete.

(S)-3-p-methoxyphenyl-3-acetamidopropan-1-ol was isolated from cultures of an actinomycete (Streptomyces michiganensis). Its structural determination by spectroscopic means and its synthesis are described.