Rob W. M. van Soest

From anti-fouling to biofilm inhibition: new cytotoxic secondary metabolites from two Indonesian Agelas sponges

Chemical investigation of Indonesian marine sponges Agelas linnaei and A. nakamurai afforded 24 alkaloid derivatives representing either bromopyrrole or diterpene alkaloids. A. linnaei yielded 16 bromopyrrole alkaloids including 11 new natural products with the latter exhibiting unusual functionalities. The new compounds include the first iodinated tyramine-unit bearing pyrrole alkaloids, agelanesins A-D. These compounds exhibited cytotoxic activity against L5178Y mouse lymphoma cells with IC(50) values between 9.25 and 16.76 muM. Further new compounds include taurine acid substituted bromopyrrole alkaloids and a new dibromophakellin derivative. A. nakamurai yielded eight alkaloids among them are three new natural products. The latter include the diterpene alkaloids (-)-agelasine D and its oxime derivative and the new bromopyrrole alkaloid longamide C. (-)-Agelasine D and its oxime derivative exhibited cytotoxicity against L5178Y mouse lymphoma cells (IC(50) 4.03 and 12.5 microM, respectively). Furthermore, both agelasine derivatives inhibited settling of larvae of Balanus improvisus in an anti-fouling bioassay and proved to be toxic to the larvae. (-)-Agelasine D inhibited the growth of planktonic forms of biofilm forming bacteria S. epidermidis (MIC<0.0877 microM) but did not inhibit biofilm formation whereas the oxime derivative showed the opposite activity profile and inhibited only biofilm formation but not bacterial growth. The structures of the isolated secondary metabolites were elucidated based on extensive spectroscopic analysis involving one- and two-dimensional NMR as well as mass spectrometry and comparison with literature data.

Sintokamides A to E, Chlorinated Peptides from the Sponge Dysidea sp. that Inhibit Transactivation of the N-Terminus of the Androgen Receptor in Prostate Cancer Cells

The new chlorinated peptides sintokamides A to E (1-5) have been isolated from specimens of the marine sponge Dysidea sp. collected in Indonesia. Their structures were elucidated by a combination of spectroscopic and single-crystal X-ray diffraction analyses. Sintokamide A (1) is an inhibitor of N-terminus transactivation of the androgen receptor in prostate cancer cells.

Chemotaxonomy of Agelas (Porifera : Demospongiae)

The secondary metabolite content of four different species of Agelas (Porifera) from the West Indies has been studied. All the compounds isolated are already known metabolites whose identification was confirmed by comparison of their spectral properties with those reported in the literature. They pertain to two different classes of compounds: terpenoids and pyrrole-2-carboxylic acid derivatives. The chemotaxonomic value of these secondary metabolites has been evaluated. Their distribution amongst the Porifera, as well as that of isocyanide derivatives, suggests a close relationship between the Agelasidae, the Axinellidae and the Halichondriidae.

Isolation of azaspiracid-2 from a marine sponge Echinoclathria sp. as a potent cytotoxin

Azaspiracid-2 was isolated from a marine sponge Echinoclathria sp. collected off Amami-Oshima as the predominant cytotoxic constituent. A combination of HPLC using ODS, GS320, and Phenylhexyl stationary phases permitted the purification without using acid or inorganic additives in the mobile phase. Azaspiracid-2 exhibited potent cytotoxicity against P388 cells with an IC50 value of 0.72 ng/mL and caused S phase arrest on the cell cycle.

Status and Perspective of Sponge Chemosystematics

In addition to their pharmaceutical applications, sponges are an important source of compounds that are used to elucidate classification patterns and phylogenetic relationships. Here we present a review and outlook on chemosystematics in sponges in seven sections: Secondary metabolites in sponges; Further applications of bioactive compound research in sponges; Sponge chemotaxonomy; Pitfalls of sponge chemotaxonomy; The chemotaxonomic suitability of sponge compounds; Potential synapomorphic markers in sponges; and The future of sponge chemotaxonomy.

Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products

The Red Sea sponge Hemimycale arabica afforded the known (Z)-5-(4-hydroxybenzylidene)-hydantoin (1), (R)-5-(4-hydroxybenzyl)hydantoin (2), and (Z)-5-((6-bromo-1H-indol-3-yl)methylene)-hydantoin (3). The natural phenylmethylene hydantoin (PMH) 1 and the synthetic (Z)-5-(4-(ethylthio)benzylidene)-hydantoin (4) showed potent in vitro anti-growth and anti-invasive properties against PC-3M prostate cancer cells in MTT and spheroid disaggregation assays. PMHs 1 and 4 also showed significant anti-invasive activities in orthotopic xenograft and transgenic mice models. To study the effect of electronic and lipophilic parameters on the activity, a wide array of several substituted aldehydes possessing electron-withdrawing (+sigma), lipophilic (+pi), electron-donating (-sigma), and less lipophilic substituents (-pi) were used to synthesize several PMHs. Few des-phenylmethylenehydantoins and 2-thiohydanoins were also synthesized and the anti-invasive activities of all compounds were evaluated. Comparative molecular field analysis (CoMFA) was then used to study the 3D QSAR. Predictive 3D QSAR model with conventional r(2) and cross validated coefficient (q(2)) values up to 0.910 and 0.651 were established. In conclusion, PMH is a novel antimetastatic lead class with potential to control metastatic prostate cancer.

5-Hydroxytryptamine-Derived Alkaloids from Two Marine Sponges of the Genus Hyrtios

Indonesian specimens of the marine sponges Hyrtios erectus and H. reticulatus were found to contain 5-hydroxytryptamine-derived alkaloids. Their structures were determined on the basis of their spectral properties. H. erectus contained hyrtiosulawesine (4), a new beta-carboline alkaloid, together with the already known alkaloids 5-hydroxyindole-3-carbaldehyde (1), hyrtiosin B (2), and 5-hydroxy-3-(2-hydroxyethyl)indole (3). H. reticulatus contained the novel derivative 1,6-dihydroxy-1,2,3,4-tetrahydro-beta-carboline (11) together with serotonin (5), 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-beta-carboline (7), and 6-hydroxy-3,4-dihydro-1-oxo-beta-carboline (9).

Gracilioethers A-C, antimalarial metabolites from the marine sponge Agelas gracilis

Three new antiprotozoan compounds, gracilioethers A-C (1-3), have been isolated from the marine sponge Agelas gracilis. Their structures were elucidated on the basis of spectroscopic and chemical methods. Gracilioethers A-C showed antimalarial activity against Plasmodium falciparum with IC(50) values of 0.5-10 microg/mL, whereas gracilioether B (2) also showed antileishmanial activity.

Strongylodiols A, B and C, new cytotoxic acetylenic alcohols isolated from the Okinawan marine sponge of the genus Strongylophora as each enantiomeric mixture with a different ratio

Three new cytotoxic long-chain acetylenic alcohols, strongylodiols A, B and C, were isolated from the Okinawan marine sponge of the genus Strongylophora. Their gross structures were elucidated based on spectroscopic analysis. During the process for determination of the absolute stereochemistry at C-6 using the modified Moshers method, these acetylenic alcohols were each found to be an enantiomeric mixture with a different ratio; 91:9 for strongylodiol A, 97:3 for strongylodiol B and 84:16 for strongylodiol C. The R configuration for each major enantiomer was established by the modified Moshers method. Each enantiomer was separated and fully characterized.

Leucettamol A : A new inhibitor of Ubc13-Uev1A interaction isolated from a marine sponge, Leucetta aff. microrhaphis

A compound that inhibits the formation of a complex composed of the ubiquitin E2 enzyme Ubc13 and Uev1A was isolated from the marine sponge Leucetta aff. microrhaphis. The compound was identified as leucettamol A (1) by spectroscopic analysis. Its inhibition of Ubc13-Uev1A interaction was tested by the ELISA method, revealing an IC(50) value of 50 microg/mL. The compound is the first inhibitor of Ubc13-Uev1A interaction, that is, that of the E2 activity of Ubc13. Such inhibitors are presumed to be leads for anti-cancer agents that upregulate activity of the tumor suppressor p53 protein. Interestingly, hydrogenation of 1 increased its inhibitory activity with an IC(50) value of 4 microg/mL, while its tetraacetate derivative was inactive, indicating that the hydroxy and/or amino groups of 1 are required for the inhibition.