Studies on the interactions of bioactive quinone avarone and its methylamino derivatives with calf thymus DNA.

The interactions of avarone, a quinone from the marine sponge Dysideaavara, and the methylamino derivatives of avarone (2), 3'-(methylamino)avarone (3) and 4'-(methylamino)avarone (4) with calf thymus DNA (CT-DNA) were studied. Agarose gel electrophoreticanalysis showed that binding of the quinones quenched fluorescence of ethidium bromide (EB). The extent of fluorescence quenching of intercalator EB by competitive displacement from EB-CT-DNA system and of groove binder Hoechst 33258 (H) from H-CT-DNA system with the quinones was analyzed by fluorescence spectroscopy. The obtained results demonstrated that the quinones reduced binding of both the intercalator EB and the minor groove binder H, indicating possible degradation of DNA. The substituent on the quinone moiety determined the extent of DNA damaging effect of the quinone, which was the most extensive with 3'-(methylamino)avarone and the least extensive with its regioisomer 4'-(methylamino)avarone. The results were confirmed by the observed hyperchromic effects in UV-visible spectra measured after interactions of the derivatives with CT-DNA.

Bioconjugate of lysozyme and the antibacterial marine sesquiterpene quinone avarone and its derivatives.

A conjugate of lysozyme with avarone, a bioactive sesquiterpene quinone of marine origin, and its three derivatives were synthesized. MALDI TOF mass spectral analysis and tryptic digestion showed that the only residue in lysozyme that was modified by all derivatives was lysine 97. The identity of the residue was in full correlation with the prediction obtained by molecular modeling. All bioconjugates preserved most of the enzymatic activity of lysozyme. The melting point of the conjugates was slightly increased in comparison to lysozyme, indicating a slight stabilization of structure. The antibacterial activity of all the conjugates to both Gram positive and Gram negative bacteria was stronger than the activity of either lysozyme or the quinones, the MIC values being in low micromolar range for some conjugates.

Synthesis and biological activity of derivatives of the marine quinone avarone.

Nine alkyl(aryl)thio derivatives of the marine sesquiterpene quinone avarone were synthesized by nucleophilic addition of thiols or thiophenol to avarone. In most cases only one regioisomer was obtained. Their cytotoxic activities, brine shrimp lethality and antibacterial activity were evaluated, as well as those of some previously synthesized avarone derivatives. Anti-HIV activity of two derivatives was tested. Electrochemical properties were determined for all the derivatives in order to obtain more accurate information on structure-activity relationships. Most derivatives showed cytotoxic activity against tumor cell lines, with IC(50) values less than 10 microM for some of them, in particular those with electron-donating substituents. The most active compound was 4'-(methylamino)avarone, with IC(50) value of 2.4 microM to melanoma Fem-X cells, and no cytotoxicity to normal lymphocytes.

Estrone derived steroidal diepoxide: biologically active compound and precursor of a stable steroidal A,B-spiro system.

A simple approach to a stable steroidal estrone derived A,B-spiro system is reported. Treatment of estrone derived A-ring diepoxyalcohol with the Ac(2)O-TMSOTf system at the ambient temperature led to acetylation, while at the reflux temperature the acid-catalysed rearrangement took place affording the spiro-compound. Results of extensive in vitro and in vivo anticancer tests on the diepoxide, as well as preliminary data on the antiproliferative activity of the spiro-product against three cancer cell lines, are also presented.

Evaluation of the activity of the sponge metabolites avarol and avarone and their synthetic derivatives against fouling micro- and macroorganisms.

The sesquiterpene hydroquinone avarol (1) was isolated from the marine sponge Dysidea avara, whereas the corresponding quinone, avarone (2), was obtained by oxidation of avarol, and the significantly more lipophilic compounds [3'-(p-chloro-phenyl)avarone (3), 3',4'-ethylenedithioavarone (4), 4'-isopropylthioavarone (5), 4'-tert-butylthioavarone (6), 4'-propylthioavarone (7), 4'-octylthioavarone (8)] were obtained by nucleophilic addition of thiols or p-chloroaniline to avarone. All these compounds were tested, at concentrations ranging from 0.5 to 50 microg/mL, for their effect on the settlement of the cyprid stage of Balanus amphitrite, for toxicity to both nauplii and cyprids and for their growth inhibitory activity on marine bacteria (Cobetia marina, Marinobacterium stanieri, Vibrio fischeri and Pseudoalteromonas haloplanktis) and marine fungi (Halosphaeriopsis mediosetigera, Asteromyces cruciatus, Lulworthia uniseptata and Monodictys pelagica).

Reactivity and biological activity of the marine sesquiterpene hydroquinone avarol and related compounds from sponges of the order Dictyoceratida.

A review of results of bioactivity and reactivity examinations of marine sesquiterpene (hydro)quinones is presented. The article is focused mostly on friedo- rearranged drimane structural types, isolated from sponges of the order Dictyoceratida. Examples of structural correlations are outlined. Available results on the mechanism of redox processes and examinations of chemo- and regioselectivity in addition reactions are presented and, where possible, analyzed in relation to established bioactivities. Most of the bioactivity examinations are concerned with antitumor activities and the mechanism thereof, such as DNA damage, arylation of nucleophiles, tubulin assembly inhibition, protein kinase inhibition, inhibition of the arachidonic cascade, etc. Perspectives on marine drug development are discussed with respect to biotechnological methods and synthesis. Examples of the recognition of validated core structures and synthesis of structurally simplified compounds retaining modes of activity are analyzed.

Synthesis and antiproliferative activity of A-ring aromatised and conduritol-like steroidal compounds.

A simple approach to aromatization of steroidal quinols and epoxyquinols using a catalytic amount of TMSOTf is reported. Beside acetylation of the angular OH, the acid-catalyzed (TfOH) dienone-phenol rearrangement occurred affording "para" products, or in the case of blocked position 4, the acetoxy group 1,2-migration leads to the formation of "meta" products. Using epoxyquinol derivative as a substrate, the acetoxy group elimination was observed, followed by acid-catalyzed epoxy-ring opening and subsequent double bond migration, giving as a final product Delta(9,11)A-ring aromatized compounds. Synthesis of conduritol-like compounds and structure confirmation by X-ray crystallography of the precursor of steroidal conduritol is also described. In addition, the results of extensive antiproliferative screening against a panel of 60 cancer cell lines are presented.

A novel lectin from the sponge Haliclona cratera: isolation, characterization and biological activity.

A lectin from the Adriatic sponge Haliclona cratera was purified by ion-exchange and gel chromatography. The molecular mass of the lectin is approximately 29 kDa. Purified lectin is rich in hydrophobic and basic amino acids and has an isoelectric point at pH 8.6. H. cratera lectin is relatively heat- and pH-stable. It agglutinates native and trypsinized, papainized and neuraminidase-treated human A, B, O, AB and sheep erythrocytes, and the hemagglutinating activity is independent of Ca(2+), Mn(2+) and Mg(2+) ions; D-galactose and N-acetyl-D-galactosamine are found to be moderate inhibitors of the activity. H. cratera lectin displays cytotoxic effect on HeLa and FemX cells and weak mitogenic effect on human T-lymphocytes pretreated with phytohemagglutinin (PHA).