Evaluation of Marine Sponge Metabolites for Cytotoxicity and Signal Transduction Activity

Abstract

Twenty-four metabolites derived from marine sponges were evaluated for their cytotoxicities against two human tumor cell lines, non-small cell lung carcinoma A549 and colon adenocarcinoma HT-29, and against one murine leukemia cell line, P-388, and evaluated for their ability to effect signal transduction in a newly developed cell adhesion assay using an EL-4 cell line. The compounds included latrunculin A [1], batzelline A [2], chondrillin [3], aureol [4], epihippuristanol, theonellamine B, discorhabdins A and C, kabiramide C, dercitin, meridine, manzamines A, B, and C, 8,15-diisocyano-11(20)-amphilectene and the corresponding C-15 formamide, a 20-carbon acetylenic alcohol, 4,5-dihydro-6"-deoxybromotopsentin, epispongiadiol, isospongiadiol, puupehenone, reiswigin A, and demethyl- and demethyloxyaaptamine. Latrunculin A [1], batzelline A [2], chondrillin [3], and aureol [4] expressed the desired profile of a greater than five-fold level of cytotoxicity against A549 relative to P-388, and an effect in the cell adhesion assay. In this group of compounds, cytotoxicity toward A549 was equal to or more pronounced than against HT-29. Latrunculin A was evaluated in an sc-implanted human A549 lung tumor xenograft mouse model and yielded a T/C of 146%. Batzelline A was evaluated in the cancer cell line panel at the National Cancer Institute and found to express selective cytotoxicity against several melanoma cancer cell lines.

Antibiotic, cytotoxic and enzyme inhibitory activity of crude extracts from Brazilian marine invertebrates

“…Our results indicate that four out of nine samples of sponges belonging to the genus Aaptos present biologically active compounds. Marine sponges belonging to the genus Aaptos are known as producers of 1H-benzo- [de][1,6]-naphtyridine alkaloids, a group of compounds which display several biological activities (Granato et al, 2000;Nakamura et al, 1982;Nakamura et al, 1987;Rudi and Kashman, 1993;Tinto, 1998;Longley et al, 1993;Shen et al, 1999;Coutinho et al, 2002;Takamatsu et al, 2003), and, therefore, compounds related to the aaptamines may be present in the samples of marine sponges herein investigated. Among them, the sponge sample Aaptos BA99-52 showed good antibacterial activity activity against oxacilin resistant S. aureus strain # 35.…”

Enantioselective total synthesis of (+)-aureol via BF3•Et2O-promoted rearrangement/cylization reaction of (+)-arenarol

“…After 1 h, the reaction was quenched with water (3 ml), and the mixture was extracted with ethyl acetate (3 x 20 ml). The combined extracts were washed with saturated aqueous sodium hydrogencarbonate and brine, then dried over MgSO 4 . Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography (hexane-ethyl acetate, 9:1) to give 6 (124 mg, 93%) as a white solid.…”

“…After 1 h, the reaction mixture was diluted with ethyl acetate (30 ml). The resulting solution was washed with 1% aqueous hydrochloric acid (2 x 5 ml) and brine, then dried over MgSO 4 1R,2S,4aR,8aS)-cis-Decahydro-1α-[(2-methoxyphenyl)methyl]-1β,2β,4aα-trimethylnaphthalen-5-one (8). 10% Pd/C (160 mg) was added to a solution of (1R,2S,4aR,8aS) -cis-decahydro-1α-[2-methoxyphenyl-1-(trifluoroacetoxy)methyl]-1β,2β,4aα-trimethyl-5-(1,3-di oxolan-2-yl)-naphthalene (7) (80.0 mg, 0.17 mmol) in methanol (5 ml), and the mixture was stirred for 25 h under hydrogen (5 atm) at room temperature.…”

“…The resulting solution was filtered through a small pad of Celite ® to remove the rest of the zinc dust. The filtrate was washed with brine, then dried over MgSO 4 . Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography (hexane-ethyl acetate, 20:1) to give 9 (32.6 mg, 82%) as a white solid.…”

“…Lithium n-butylthiolate in HMPA (0.5M solution, 4.80 ml, 2.40 mmol) was added to a stirred solution of (1R,2S,4aR,8aS)-cis-decahydro-1α-[(2-methoxyphenyl)methyl]-1β,2β,4aα-trimethyl-5-methylenenaphthalene (9) (51.0 mg, 0.16 mmol) in HMPA (0.6 ml) at room temperature, and the mixture was heated at 90°C for 2 h. After cooling, the reaction was quenched with saturated aqueous ammonium chloride (1 ml), and the resulting mixture was extracted with ethyl acetate (3 x 15 ml). The combined extracts were washed with brine, then dried over MgSO 4 2-[(1R,2S,4aR,8aS)-cis-Decahydro-1β,2β,4aα-trimethyl-5-methylene-naphthalen-1-yl-meth yl]-benzene-1,4-diol (2) (arenarol). Sodium hydrosulfite (159 mg, 0.92 mmol) was added to a stirred solution of 2-[(1R,2S,4aR,8aS)-cis-decahydro-1β,2β,4aα-trimethyl-5-methylenenaphthalen-1-yl-methyl] - [1,4]benzoquinone (11) (arenarone) (28.6 mg, 92 µmol) in THF (3.2 ml) containing water (1.6 ml) at 0°C.…”