Cortamidine oxide, a novel disulfide metabolite from the New Zealand basidiomycete (mushroom) Cortinarius species.

Three disulfide metabolites were isolated from the fruiting bodies of the basidiomycete (mushroom) Cortinarius sp., collected in the Catlins, New Zealand. The structures of these compounds were determined as the unsymmetrical disulfide cortamidine oxide (1), 2,2'-dithiobis(pyridine N-oxide) (2), and the symmetrical disulfide 3. Both 1 and 2 showed significant antimicrobial activity and cytotoxicity. 2,2'-Dithiobis(pyridine N-oxide) (2) and the symmetrical disulfide 3 are assumed to be artifacts of the isolation procedure.

Some ways of looking at compensatory kosmotropes and different water environments.

Hydration of macromolecular structures determines biological activity. Stabilizing solutes are kosmotropic (increase order of water) rather than chaotropic (decrease order). Preferential hydration of surfaces is a thermodynamic consequence of the solution behavior of kosmotropic solutes, but inconsistencies imply interactions such as the hydration of specific sites within macromolecules. Thermodynamic measures require bulk pure solutes; here simpler measures of the effects on bulk water, water at surfaces and hydration water of probes have been applied to solutes including natural stabilizers, analogues and example chaotropes. Changes in the near-infrared spectra, water proton NMR chemical shifts and relaxation times measure changes in the bulk liquid; HPLC-column retention of solutes indicate interactions with hydration water at different surfaces, and fluorescence probes detect effects on functional group hydration water. Ab initio calculations and Monte-Carlo simulations of the solutes in water measure the energetics of the solute-water interactions, the dipole moments of these molecules, their charge distributions and the effect of the solute molecules on the structure of water. The rankings of the test solutes by these measures are not consistent. Thus, stabilizing solutes are not interchangeable in biological systems and the intracellular replacement of one by another could affect the integration of cell metabolism.

Mycalamides C and D, cytotoxic compounds from the marine sponge Stylinos n. species.

The new cytotoxic compounds, mycalamides C (3) and D (4), have been isolated from the marine sponge Stylinos n. sp., along with the known theopederin E (1) and mycalamide A (2).

The discovery and development of marine compounds with pharmaceutical potential.

An assessment of the current status of marine anticancer compounds is presented along with a case study on the aquaculture of Lissodendoryx n. sp. 1, a sponge that produces the antimitotic agents halichondrin B and isohomohalichondrin B. The use of polymer therapeutics to enhance the properties of marine natural products is considered.

Alertenone, a dimer of suberosenone from Alertigorgia sp.

Bioassay-guided fractionation of organic extracts of the gorgonian Alertigorgia sp. has yielded the previously known suberosenone (1), a cytotoxic tricyclic sesquiterpene of the quadrone class, and alertenone (2), a dimer of suberosenone. The structure of 2 was determined by spectral analysis; the 1D TOCSY experiment was particularly useful in the structure elucidation. Comparison of the in vitro cytotoxicity of alertenone and suberosenone revealed that the dimeric alertenone was devoid of cytotoxicity below 35 microg/mL. In a hollow-fiber assay model of in vivo activity, suberosenone exhibited some growth inhibition of two of six tumor cell lines tested.

Guttiferone F, the first prenylated benzophenone from Allanblackia stuhlmannii.

The HIV-inhibitory activity in extracts of Allanblackia stuhlmannii was tracked, via bioassay-guided fractionation, to a new member of the camboginol/guttiferone class of prenylated benzophenones, guttiferone F (1). The structure was solved by extensive NMR analyses and by acid-catalyzed conversion to 30-epi-cambogin (4). This is the first report of this compound type in the genus Allanblackia.

Theonellapeptolide IIIe, a new cyclic peptolide from the New Zealand deep water sponge, Lamellomorpha strongylata.

The structure, stereochemistry, and conformation of theonellapeptolide IIIe (1), a new 36-membered ring cyclic peptolide from the New Zealand deep-water sponge Lamellomorpha strongylata, is described. The sequence of the cytotoxic peptolide was determined through a combination of NMR and MS-MS techniques and confirmed by X-ray crystal structure analysis, which, with chiral HPLC, established the absolute stereochemistry.

Nuclear magnetic resonance characterization of 6 alpha-chloro-5 beta-cholestane-3 beta,5-diol formed from the reaction of hypochlorous acid with cholesterol.

Hypochlorous acid generated by neutrophil myeloperoxidase has been shown to convert cholesterol into three different chlorohydrin isomers which previously had not been fully characterized. We have reacted hypochlorous acid with cholesterol/1,2-dipalmitoyl phosphatidylcholine liposomes to give these three major products and established that they are 6 beta-chloro-5 alpha-cholestane-3 beta,5-diol (chlorohydrin 1), 5 alpha-chloro-6 beta-cholestane-3,6-diol (chlorohydrin 2) and 6 alpha-chloro-5 beta-cholestane-3 beta,5-diol (chlorohydrin 3). These products were separated by thin-layer chromatography and fully characterized by 1H, 13C, attached proton test, doublequantum correlation spectroscopy, total correlation spectroscopy, heteronuclear multiple bond correlation and heteronuclear multiple quantum coherence nuclear magnetic resonance spectroscopy.

Anti-HIV michellamines from Ancistrocladus korupensis.

Here we report details of the isolation and determination of the absolute configurations and comparative anti-HIV activities of novel, atropisomeric naphthylisoquinoline alkaloid dimers, michellamines A, B, and C, from a newly described species of Ancistrocladus from the Korup rainforest of Cameroon. We further provide a more extensive analysis of the range of anti-HIV activity of michellamine B, the most potent and abundant member of the series. Michellamine B inhibited HIV-induced cell killing and viral replication in a variety of human cell lines, as well as in cultures of human peripheral blood leukocytes and monocytes. Michellamine B was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6 and the pyridinone-resistant strain A17; the compound also inhibited several strains of HIV-2.

New cytotoxic beta-carboline alkaloids from the marine bryozoan, Cribricellina cribraria.

Bioactivity-directed separations led to the isolation of the new alkaloid, 1-vinyl-8-hydroxy-beta-carboline [1], as the major cytotoxic component of the marine bryozoan Cribricellina cribraria. Another new beta-carboline alkaloid 2 with the novel sulfone structure was isolated, together with a number of known beta-carboline compounds. Cytotoxicity and antimicrobial effects are reported for these compounds and for other synthesized beta-carbolines.

A cytotoxic and antifungal 1,4-naphthoquinone and related compounds from a New Zealand brown algae, Landsburgia quercifolia.

The bioactivity-directed isolation of deoxylapachol [I] from a New Zealand brown alga, Landsburgia quercifolia, is described. Compound I was active against P-388 leukemia cells (IC50 0.6 microgm/ml) and was also antifungal. 1,4-Dimethoxy-2-(3-methyl-2-butenyl)-naphthalene [3] was the major low polarity component of extracts of this seaweed, which also contained 2,3-dihydro-2,2-bis(3-methyl-2-butenyl)-1,4-naphthalenedione [6] and 2-(3-methyl-2-butenyl)-2,3-epoxy- 1,4-naphthalenedione 4,4-dimethoxy ketal [7]. Compound 7 was converted to the 2,3-epoxide of I, which had biological activities similar to those of I.

4-Hydroxy-2-cyclopentenone: an anti-Pseudomonas and cytotoxic component from Passiflora tetrandra.

4-Hydroxy-2-cyclopentenone is responsible for the anti-bacterial activity of an extract of leaves from Passiflora tetrandra with minimum inhibitory doses (MID) of ca. 10 micrograms/disk against Escherichia coli, Bacillus subtilis, and Pseudomonas aeruginosa. 4-Hydroxy-2-cyclopentenone is also cytotoxic to P388 murine leukemia cells (IC50 of less than 1 microgram/ml).

Assignment of aromatic resonances in the 1H nuclear magnetic resonance spectra of cardioactive polypeptides from sea anemones.

High-resolution 1H NMR spectroscopy at 300 MHz has been used to investigate the aromatic residues of a series of homologous polypeptides from sea anemones: anthopleurin-A from Anthopleura xanthogrammica and toxins I and II from Anemonia sulcata. Using two-dimensional NMR techniques, specific assignments to individual protons have been made for all aromatic resonances in the spectra of these molecules. In all three polypeptides the resonances from the two conserved Trp residues, 23 and 33, are shifted significantly from their random coil values, and the indole NH resonance of Trp-23 is not observed. These shift perturbations are due in part to a mutual interaction of the two indole rings, which is also indicated by the observation of nuclear Overhauser enhancements between protons of the two rings. Several other nonpolar side chains also interact with these two Trp residues, forming a hydrophobic region, the overall structure of which is conserved throughout the series. The other aromatic residues in these polypeptides appear not to participate in this structural region.

Ceroid lipofuscinosis in sheep. I. Bis(monoacylglycero)phosphate, dolichol, ubiquinone, phospholipids, fatty acids, and fluorescence in liver lipopigment lipids.

The ceroid lipofuscinoses are inherited lysosomal diseases of children characterized by a fluorescent lipopigment stored in a variety of tissues. Defects in lipid metabolism or the control of lipid peroxidation have been postulated to explain their pathogenesis. In the present study, lipopigment was isolated from the liver of sheep affected with ceroid lipofuscinosis. It was 70% protein, the rest being mainly lipids. These were only one-sixth as fluorescent as total liver lipids, but contained a number of fluorophors. None were major components of the lipopigment or the postulated fluorescent product of lipid peroxidation. Lipopigment lipids included the lysosomal marker bis(monoacylglycero)phosphate that contained 42.9% linoleate and 16.5% linolenate. Lipopigment neutral lipids were dolichol, dolichyl esters, ubiquinone, free fatty acids, and cholesterol, indicative of a lysosomal origin of the lipopigment. Phosphatidylcholine, phosphatidylinositol, phosphatidylserine, and phosphatidylethanolamine were present in proportions and with fatty acid profiles typical of lysosomes. No differences were found between the lipids of total control and affected livers, nor the fatty acid profiles of their phosphatidylcholine, phosphatidylethanolamine, or triglycerides. It is concluded that ovine ceroid lipofuscinosis is not a lipidosis, nor does the lipopigment arise from the abnormal peroxidation of lipids. Strong similarities between the lipopigment and the age pigment lipofuscin were noted.

Conformational heterogeneity in polypeptide cardiac stimulants from sea anemones.

High-resolution 1H NMR spectra at 300 MHz of the polypeptide cardiac stimulants anthopleurin-A and Anemonia sulcata toxin II reveal conformational heterogeneity in both molecules. The two conformations, manifest in a number of split 1H resonances, are in slow exchange over a wide range of pH and temperature. Heterogeneity affects a region of these molecules containing the structurally and functionally important Asp residues. By comparison with a homologous polypeptide Anemonia sulcata toxin I, which does not show this type of heterogeneity, it is suggested that the heterogeneity may originate in cis-trans isomerism of the Gly-40 to Pro-41 peptide bond.