Characterization of non-dialyzable constituents from cranberry juice that inhibit adhesion, co-aggregation and biofilm formation by oral bacteria.

An extract prepared from cranberry juice by dialysis known as nondialyzable material (NDM) has been shown previously to possess anti-adhesion activity toward microbial species including oral bacteria, uropathogenic Escherichia coli and Helicobacter pylori. Bioassay-guided fractionation of cranberry NDM was therefore undertaken to identify the anti-adhesive constituents. An aqueous acetone-soluble fraction (NDMac) obtained from Sephadex LH-20 inhibited adhesion-linked activities by oral bacteria, including co-aggregation of oral bacteria Fusobacterium nucleatum with Streptococcus sanguinis or Porphyromonas gingivalis, and biofilm formation by Streptococcus mutans. Analysis of NDMac and subsequent subfractions by MALDI-TOF MS and 1H NMR revealed the presence of A-type proanthocyanidin oligomers (PACs) of 3-6 degrees of polymerization composed of (epi)catechin units, with some (epi)gallocatechin and anthocyanin units also present, as well as quercetin derivatives. Subfractions containing putative xyloglucans in addition to the mixed polyphenols also inhibit biofilm formation by S. mutans (MIC = 125-250 µg mL-1). These studies suggest that the anti-adhesion activities of cranberry NDM on oral bacteria may arise from a combination of mixed polyphenol and non-polyphenol constituents.

Salarin C inhibits the maintenance of chronic myeloid leukemia progenitor cells.

We previously showed that incubation of chronic myeloid leukemia (CML) cells in very low oxygen selects a cell subset where the oncogenetic BCR/Abl protein is suppressed and which is thereby refractory to tyrosine kinase inhibitors used for CML therapy. In this study, salarin C, an anticancer macrolide extracted from the Fascaplysinopsis sponge, was tested as for its activity on CML cells, especially after their incubation in atmosphere at 0.1% oxygen. Salarin C induced mitotic cycle arrest, apoptosis and DNA damage. Salarin C also concentration-dependently inhibited the maintenance of stem cell potential in cultures in low oxygen of either CML cell lines or primary cells. Surprisingly, the drug also concentration-dependently enforced the maintenance of BCR/Abl signaling in low oxygen, an effect which was paralleled by the rescue of sensitivity of stem cell potential to IM. These results suggest a potential use of salarin C for the suppression of CML cells refractory to tyrosine kinase inhibitors.

Effects of natural and novel synthetic jasmonates in experimental metastatic melanoma.

BACKGROUND AND PURPOSE: No current treatment reliably affects the course of metastatic melanoma. Consequently, novel approaches to the control of metastasis are actively sought. The overall goal of the present study was to identify new anti-metastatic agents active against melanoma cells. EXPERIMENTAL APPROACH: Two directions were taken: 1. To determine whether the natural plant hormone methyl jasmonate, which kills cancer cells selectively, can suppress the characteristic metastatic behavior of B16-F10 melanoma cells; 2. To synthesize and identify novel jasmonate derivatives with better cytotoxic and anti-metastatic activities than methyl jasmonate. KEY RESULTS: We found that methyl jasmonate suppressed B16-F10 cell motility and inhibited the development of experimental lung metastases of these cells. Furthermore, methyl jasmonate suppressed the motility of a sub-clone of these cells over-expressing P-glycoprotein and exhibiting multidrug resistance. The synthetic derivative Compound I (5,7,9,10-tetrabromo derivative of methyl jasmonate, the most active derivative) had greater cytotoxic potency (IC(50), 0.04 mM) than methyl jasmonate (IC(50), 2.6mM). Compound I prevented B16-F10 cell adhesion efficiently and inhibited the development of lung metastases at a much lower dose than methyl jasmonate. CONCLUSIONS AND IMPLICATIONS: Natural and synthetic jasmonates have anti-metastatic actions. Further development of these agents for the suppression of metastasis in melanoma and other types of cancer is warranted.

Clathsterol, a novel anti-HIV-1 RT sulfated sterol from the sponge Clathria species.

As part of a search for novel inhibitors of humandeficiency virus type 1 (HIV-1) reverse transcriptase (RT), the MeOH-EtOAc extract of a Red Sea sponge, Clathria sp., was shown to be active. Bioassay-guided fractionation of the extract yielded a novel sterol sulfate, clathsterol (1), which is responsible for the activity and is active at a concentration of 10 microM. The structure of 1 was established mainly by interpretation of spectral data and a chemical transformation.

Suppressors of cancer cell proliferation from fig (Ficus carica) resin: isolation and structure elucidation.

A mixture of 6-O-acyl-beta-D-glucosyl-beta-sitosterols, the acyl moeity being primarily palmitoyl and linoleyl with minor amounts of stearyl and oleyl, has been isolated as a potent cytotoxic agent from fig (Ficuscarica) latex and soybeans. Identity was established by spectroscopic methods (NMR, MS) and confirmed by chemical synthesis. Both the natural and the synthetic compounds showed in vitro inhibitory effects on proliferation of various cancer cell lines.

New triterpenoids from the Red Sea sponge Siphonochalina siphonella.

Clear differences were found when comparing the chemical content of the northern, Gulf of Eilat, to the southern-central, Dahlak archipelago, Red Sea sponge Siphonochalina siphonella. The Dahlak sponge was found to be richer in the more polar triterpenes. Nine new compounds (1-4, 7, 8, 15-17) were isolated and identified, among them two sipholane glycosides, sipholenoside A and B (7 and 8), and one compound, dahabinone A (17), possessing a new skeleton.

Aplyzanzine A, a new dibromotyrosine derivative from a Verongida sponge.

Aplyzanzine A (1), a novel bisdibromotyrosine derivative, has been isolated from the Indo-Pacific sponge Aplysina sp. Its structure was elucidated mainly on the basis of 1D and 2D NMR and MS spectroscopic data.

Bacteriohopanehexol, a new triterpene from the marine sponge Petrosia species.

A new bacteriohopanoid, bacteriohopanehexol was isolated from the marine sponge Petrosia sp., and its structure 1a was established on the basis of the NMR and MS spectroscopic data of its hexaacetate derivative 1b. Bacteriohopanehexol is most likely a bacterial metabolite.

Clathculins A and B, two novel nitrogen-containing metabolites from the sponge Clathrina aff. reticulum.

Two novel acyclic diaza alkenynes, clathculins A and B (1 and 2), were isolated from the Indo-Pacific sponge Clathrina aff. reticulum collected in Sodwana Bay, South Africa. The structure of the mixture of the two unstable inseparable compounds was established by spectroscopic analysis, mainly 1D and 2D NMR measurements and two chemical transformations. Clathculins A and B are the first reported linear marine metabolites containing a 1,2-diaminoethane moiety.

Cycloshermilamine D, a new pyridoacridine from the marine tunicate cystodytes violatinctus.

A new alkaloid, cycloshermilamine D, was isolated from the marine tunicate Cystodytes violatinctus, and its structure (1), which is closely related to shermilamine D, was established mainly on the basis of NMR spectroscopic data.

Polycitone B and prepolycitrin A: two novel alkaloids from the marine ascidian Polycitor africanus.

Two novel compounds, polycitone B (4) and prepolycitrin A (3), were isolated from the marine ascidian Polycitor africanus. The structures of these new dibromotyrosine metabolites were established mainly on the basis of NMR spectroscopic data. Isolation of compound 3 supports the earlier suggestion that it is the bioprecursor of polycitrin A (2).

Haliclonyne, a new highly oxygenated polyacetylene from the marine sponge Haliclona species.

Haliclonyne (1), a new polyacetylene carboxylic acid, has been isolated from the marine sponge Haliclona sp. collected in the Gulf of Eilat. The structure of haliclonyne, a C(47) oxo-octahydroxy-dienetetrayne carboxylic acid, was elucidated by interpretation of NMR and mass spectra of 1 and two of its derivatives.

Asmarines A-F, novel cytotoxic compounds from the marine sponge Raspailia species.

Three pairs of nitrogen-containing metabolites, asmarines A-F (1-6), were isolated from the Red Sea sponge Raspailia sp., collected in the Dahlak Archipelago, Eritrea. Although the first pair could fully be separated to give compounds 1 and 2, the other two pairs could only be enriched up to about 80% of one isomer. The structures of the new compounds were established by spectroscopic means. Besides the asmarines, methyl 3-oxo-cholan-24-oate (12) was also isolated. The absolute configuration of asmarine A (1) was determined on the basis of CD measurements of its unstable 18-oxo derivative (7) and mainly the Cotton effect of the dicarbonyl derivative (9) of chelodane (8). A O,N(7')-dimethyl derivative (10) and a second, unexpected, methylated product (11) were obtained from 2.

Hydroquinone antioxidants from the Indian ocean tunicate Aplidium savignyi.

Three hydroquinone compounds have been isolated from the Indian Ocean tunicate Aplidium savignyi. Two are already known: geranylhydroquinone and the 2-(3-hydroxy-3,7-dimethyloct-6-enyl)-1,4-benzenediol as a new stereoisomer 2-(2Z)-(3-hydroxy-3, 7-dimethyloct-2,6-dienyl)-1,4-benzenediol. The structures were determined using spectroscopic data ((1)H NMR, (13)C NMR, MS, UV, and IR). These compounds are potential natural antioxidants.

Polycitone A, a novel and potent general inhibitor of retroviral reverse transcriptases and cellular DNA polymerases.

Polycitone A, an aromatic alkaloid isolated from the ascidian Polycitor sp. exhibits potent inhibitory capacity of both RNA- and DNA-directed DNA polymerases. The drug inhibits retroviral reverse transcriptase (RT) [i.e. of human immunodeficiency virus type 1 (HIV), murine leukaemia virus (MLV) and mouse mammary tumour virus (MMTV)] as efficiently as cellular DNA polymerases (i.e. of both DNA polymerases alpha and beta and Escherichia coli DNA polymerase I). The mode and mechanism of inhibition of the DNA-polymerase activity associated with HIV-1 RT by polycitone A have been studied. The results suggest that the inhibitory capacity of the DNA polymerase activity is independent of the template-primer used. The RNase H function, on the other hand, is hardly affected by this inhibitor. Polycitone A has been shown to interfere with DNA primer extension as well as with the formation of the RT-DNA complex. Steady-state kinetic studies demonstrate that this inhibitor can be considered as an allosteric inhibitor of HIV-1 RT. The target site on the enzyme may be also spatially related to the substrate binding site, since this inhibitor behaves competitively with respect to dTTP with poly(rA).oligo(dT) as template primer. Chemical transformations of the five phenol groups of polycitone A by methoxy groups have a determinant effect on the inhibitory potency. Thus, the pentamethoxy derivative which is devoid of all hydroxy moieties, loses significantly, by 40-fold, the ability to inhibit the DNA polymerase function. Furthermore, this analogue lacks the ability to inhibit DNA primer extension as well as the formation of the RT-DNA complex. Indeed, inhibition of the first step in DNA polymerization, the formation of the RT-DNA complex, and hence, of the overall process, could serve as a model for a universal inhibitor of the superfamily of DNA polymerases.

Bilosespens A and B: two novel cytotoxic sesterpenes from the marine sponge Dysidea cinerea.

[formula: see text] Two novel sesterpenes, bilosespens A and B (1 and 2) were isolated from the Red Sea sponge Dysidea cinerea collected in the Dahlak archipelago, Eritrea. The structure of the mixture of the two inseparable compounds was established by spectroscopic analysis, mainly by 1D and 2D NMR measurements. The mixture of bilosespens A and B is cytotoxic to a few human cancer cells.

Isolation and Identification of a New Antifungal Sesquiterpene Lactone from Inula viscosa.

A new sesquiterpene - tayunin - has been isolated and purified from powdered leaves of INULA VISCOSA (L.) Ait. The chemical structure was determined by 1D and 2D NMR analysis, and IR and MS. Tayunin inhibits the growth of MICROSPORUM CANIS at a concentration of 10 microg/ml and TRICHOPHYTON RUBRUM at 50 microg/ml(MIC).

Bebryazulene, a new guaiane metabolite from the indian ocean gorgonian coral, bebryce grandicalyx

Bebryazulene (1), a new sesquiterpene having the guaiane skeleton, was isolated from the methanol-chloroform 1:2 extract of the Indian Ocean gorgonian coral Bebryce grandicalyx (Kuekenthal) collected in the lagoon of Mayotte. Structure assignment was based on interpretation of spectroscopic data. This new metabolite was very labile and reacted with 4-phenyl-3H-1,2,4-triazoline-3,5-dione to yield an unexpected adduct.

Several new isoprenoids from the soft coral sinularia erecta

Eight compounds were isolated from the Indo-Pacific soft coral Sinularia erecta (Tixier-Durivault, 1945) collected from the lagoon of Mayotte, Comoros Islands, northwest of Madagascar. Four of the compounds, namely the sesquiterpene germacrene D, the diterpenoids nephthenol and decaryiol, and norcembrene, are known. The other four are the new secondary metabolites germacrene E (1), epi-norcembrene (3), and two bis-pukalide diterpenes, mayotolides A and B (4 and 5). The structure of each of the compounds was determined by means of 1D and 2D NMR and MS spectroscopy in addition to some chemical transformations.