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The Caribbean sea whip Pseudopterogorgia elisabethae (Octocorallia, Cnidaria) has been found to contain the pseudopterosins, a newly described class of natural products, which have been characterized as diterpene-pentoseglycosides. The pseudopterosins possess anti-inflammatory and analgesic properties that exceed, in our assays, the potencies of existing drugs such as indomethacin. As anti-inflammatory agents, the pseudopterosins appear to modify the arachidonic acid cascade by an as yet undefined mechanism of pharmacological action.As part of a continuing program to explore the chemical adaptations of marine organisms and to assess the biomedical applications of marine metabolites, we have focused considerable attention on the chemically rich sea fans and whips (gorgonian soft-corals) found in the Caribbean Sea (1-5). During an expedition on board the research vessel Calanus,5 our attention was drawn to several sea whips of the genus Pseudopterogorgia found generally at depths in excess of 20 m. The highly branched Pseudopterogorgia elisabethae was ofparticular interest since ship-board chemical and biological assays revealed this animal to contain large quantities of unknown, polar-lipid metabolites that were apparently coupled with strong inhibitory activities in field-oriented antimicrobial and cytotoxicity assays.bc Subsequent mass collection, extraction, and fractionation of the extract of P. elisabethae has now resulted in the isolation of pseudopterosins A-D (14), highly bioactive diterpenoid glycosides, which are responsible for these potent activities.Chemistry of the Pseudopterosins Purification of pseudopterosins A-D was achieved by sequential silica gel chromatography including HPLC. Pseudopterosin A (1), the most polar metabolite, was assigned the molecular formula C25H3606 by high-resolution mass spectrometry and by analysis of 13C NMR data ( Table 1). The eight degrees of unsaturation in this molecular formula were assigned to a fully substituted benzene ring, one trisubstituted olefinic bond (gem-dimethyl), a cyclic hemiacetal, and two carbocyclic rings on the basis of NMR and other spectral data.d Characteristic 13C NMR features, infrared spectral data for hydroxyl (ca. 3400 cm-1), and a base-induced bathochromic shift of the UV absorption of 1 showed this metabolite to be phenolic.Acetylation of pseudopterosin A (Ac20/py/RT) yielded a tetraacetate, 5, which proved that 1 contained at least four hydroxyl groups. In a consistent fashion, acetylation of each of the pseudopterosins, B(2), C(3), and D(4), produced the same tetraacetate, 5, in nearly quantitative yield. Since the molecular formulas of these latter compounds were that of pseudopterosin A (C25H3606) + C2H20, the less polar pseudopterosins were concluded to be monoacetate positional isomers of 1.Inspection of the high resolution mass spectrometry data for 1 showed that the base peak represented M+ -C5H804fragmentation. This behavior, coupled with the presence of three nonphenolic hydroxyl groups and an acetal constellation, st...

Marine natural products provide a rich source of chemical diversity that can be used to design and develop new, potentially useful therapeutic agents. We report here that scytonemin, a pigment isolated from cyanobacteria, is the first described small molecule inhibitor of human polo-like kinase, a serine/threonine kinase that plays an integral role in regulating the G 2 /M transition in the cell cycle. Scytonemin inhibited polo-like kinase 1 activity in a concentration-dependent manner with an IC 50 of 2 M against the recombinant enzyme. Biochemical analysis showed that scytonemin reduced GST-polo-like kinase 1 activity in a time-independent fashion, suggesting reversibility, and with a mixed-competition mechanism with respect to ATP. Although scytonemin was less potent against protein kinase A and Tie2, a tyrosine kinase, it did inhibit other cell cycle-regulatory kinases like Myt1, checkpoint kinase 1, cyclin-dependent kinase 1/cyclin B, and protein kinase C␤2 with IC 50 values similar to that seen for polo-like kinase 1. Consistent with these effects, scytonemin effectively attenuated, without chemical toxicity, the growth factor-or mitogen-induced proliferation of three cell types commonly implicated in inflammatory hyperproliferation. Similarly, scytonemin (up to 10 M) was not cytotoxic to nonproliferating endotoxin-stimulated human monocytes. In addition, Jurkat T cells treated with scytonemin were induced to undergo apoptosis in a non-cell cycle-dependent manner consistent with its activities on multiple kinases. Here we propose that scytonemin's dimeric structure, unique among natural products, may be a valuable template for the development of more potent and selective kinase inhibitors used for the treatment of hyperproliferative disorders.

Eighty-four analogues and derivatives of the acetylcholine-storage-blocking drug trans-2-(4-phenylpiperidino)-cyclohexanol (vesamicol) were synthesized, and their potencies were evaluated with the acetylcholine active-transport assay utilizing purified synaptic vesicles from Torpedo electric organ. The parent drug exhibits enantioselectivity, with (-)-vesamicol being 25-fold more potent than (+)-vesamicol. The atomic structure and absolute configuration of (+)-vesamicol were determined by X-ray crystallography. The absolute configuration of (-)-vesamicol is 1R,2R. Structure-activity evidence indicates that (-)-vesamicol does not act as an acetylcholine analogue. Alterations to all three rings can have large effects on potency. Unexpectedly, analogues locking the alcohol and ammonium groups trans-diequatorial or trans-diaxial both exhibit good potency. A potent benzovesamicol family has been discovered that is suitable for facile elaboration of the sort useful in affinity labeling and affinity chromatography applications. A good correlation was found between potencies as assessed by the acetylcholine transport assay and LD50 values in mouse.