Homophymines B-E and A1-E1, a family of bioactive cyclodepsipeptides from the sponge Homophymia sp.

Nine new cyclodepsipeptides, homophymines B-E (2-5) and A1-E1 (1a-5a), were isolated from the polar extracts of the sponge Homophymia sp. The new structures, featuring new polyketide-derived end groups, were determined by interpretation of NMR and MS data. The configurations of the new end groups was secured by the application of J-based configurational analysis. Homophymines displayed very potent antiproliferative activity (IC(50) in the nM range) against a panel of human cancer cell lines.

Homophymine A, an anti-HIV cyclodepsipeptide from the sponge Homophymia sp.

A new anti-HIV cyclodepsipeptide, homophymine A, was isolated from a New Caledonian collection of the marine sponge Homophymia sp. The structure of homophymine A was determined by interpretation of spectroscopic data, acid hydrolysis, and LC-MS analysis. Homophymine A contains 11 amino acid residues and an amide-linked 3-hydroxy-2,4,6-trimethyloctanoic acid moiety. Along with four D-, two L-, and one N-methyl amino acids, it also contains four unusual amino acid residues: (2S,3S,4R)-3,4-diMe-Gln, (2R,3R,4S)-4-amino-2,3-dihydroxy-1,7-heptandioic acid, L-ThrOMe, and (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid. In a cell-based XTT assay, homophymine A exhibited cytoprotective activity against HIV-1 infection with a IC50 of 75 nM.

Girolline interferes with cell-cycle progression, but not with translation.

Girolline is a 2-aminoimidazole derivative with cytotoxic activity. It affects the survival of exponentially growing leukaemic cultured cells and has a significant antitumour activity on grafted murine tumours in vivo. In vitro studies showed that girolline affected protein synthesis by interfering with the translation termination process. Here, we investigate the effect of girolline on translation termination in human cultured cells. We show that girolline neither induces an increase in translational readthrough of stop codons nor affects the polysome profile in treated cells. This suggests that girolline does not act on translation in vivo. Then, we examine the effect of girolline on cell-cycle progression and we show that girolline induces an arrest of the cell cycle at the G2 stage.

Indole and aminoimidazole moieties appear as key structural units in antiplasmodial molecules.

From a library of compounds of natural sources, a big series of molecules was chosen by random sampling to evaluate their in vitro antimalarial activity against Plasmodium falciparum and their antifungal activity against Candida sp. From 184 molecules tested, no molecules were active against Candida sp. (MIC>10µg/ml) whereas 13 clearly showed high antiplasmodial activity in vitro, with an IC(50) less than 1µg/ml against the chloroquine-resistant strain of P. falciparum FcM29-Cameroon. The molecules with the best antiplasmodial efficacy were 10-hydroxy-ellipticin (IC(50): 0.08µg/ml), tchibangensin (IC(50): 0.13µg/ml), ellipticin hydrochloride (IC(50): 0.17µg/ml), usambarensin (IC(50): 0.23µg/ml), 7S,3S-ochropposinine oxindole (IC(50): 0.25µg/ml), 3,14-dihydro-ellipticin (IC(50): 0.25µg/ml), tetrahydro-4',5',6'17-usambarensin 17S (IC(50): 0.26µg/ml), ellipticine (IC(50): 0.28µg/ml), aricin (IC(50): 0.3µg/ml), 10-methoxy-ellipticin (IC(50): 0.32µg/ml), aplysinopsin (IC(50): 0.43µg/ml), descarbomethoxydihydrogambirtannin (IC(50): 0.46µg/ml) and ochrolifuanin A (IC(50): 0.47µg/ml). Among these 13 promising molecules, all except descarbomethoxydihydrogambirtannin, ochrolifuanine A and usambarensine presented here novel biological activities since they had never been described in the literature for their antiplasmodial activity. In spite of the large diversity of the molecules which have been tested, it is interesting to note that the ones active against Plasmodium are all indole derivatives (and one is both indolic and aminoimidazolic). To find new antiplasmodial compounds, ethnopharmacological approaches studying traditional medicine treatments for malaria is largely used but random research produced here an interesting yield (7%) of new antiplasmodial hits and appears therefore complementary to the traditional medicine way.

Girolline: a potential lead structure for antiplasmodial drug research.

Girolline is a 2-aminoimidazole derivative extracted from Cymbastela cantharella (a New-Caledonian sponge) that has shown antitumor activity. In this study, we investigated its antimalarial activity and the point of action within the erythrocytic cycle of Plasmodium falciparum. Initially, we tested girolline and some synthetic analogues in vitro against four P. falciparum strains. The IC (50) values of girolline ranged from 77 to 215 nM, and as with artemisinin or chloroquine, girolline inhibited parasitic growth by 100 %. Girolline was found to be active at a dose of 1 mg/kg/d (orally and intraperitoneally) in vivo. Moreover, there was a significant synergistic effect between girolline and chloroquine in vitro. The investigation of the mechanism of action of girolline during the erythrocytic life cycle of the parasite showed that its action targets the synthesis of proteins by the parasite. With such a biological profile, girolline could be considered as a model chemical structure for new candidates in the arsenal of new drugs and in particular of drugs able to fight malaria.

Time-dependent inhibitors of trypanothione reductase: analogues of the spermidine alkaloid lunarine and related natural products.

The macrocyclic spermidine alkaloid lunarine 1 from Lunaria biennis is a competitive, time-dependent inhibitor of the protozoan oxidoreductase trypanothione reductase (TryR), a promising target in drug design against tropical parasitic diseases. Various molecules related to 1 and the alkaloid itself have been synthesized in racemic form and evaluated against TryR in order to determine the key features of 1 that are associated with time-dependent inhibition. Kinetic data are consistent with an inactivation mechanism involving a conjugate addition of an active site cysteine residue onto the C-24-C-25 double bond of the tricyclic nucleus of 1. Comparison of data for synthetic (+/-)-1, the natural product, and other derivatives 7-10 from L. biennis confirms the importance of the unique structure of the tricyclic core as a motif for inhibitor design and reveals that the non-natural enantiomer may be a more suitable scaffold upon which thiophilic groups may be presented.