Aaptamines from the marine sponge Aaptos sp. display anticancer activities in human cancer cell lines and modulate AP-1-, NF-κB-, and p53-dependent transcriptional activity in mouse JB6 Cl41 cells.

Aaptamine (8,9-dimethoxy-1H-benzo[de][1,6]naphthyridine) is a marine natural compound possessing antioxidative, antimicrobial, antifungal, and antiretroviral activity. Earlier, we have found that aaptamine and its derivatives demonstrate equal anticancer effects against the human germ cell cancer cell lines NT2 and NT2-R and cause some changes in the proteome of these cells. In order to explore further the mechanism of action of aaptamine and its derivatives, we studied the effects of aaptamine (1), demethyl(oxy)aaptamine (2), and isoaaptamine (3) on human cancer cell lines and on AP-1-, NF-κB-, and p53-dependent transcriptional activity in murine JB6 Cl41 cells. We showed that compounds 1-3 demonstrate anticancer activity in THP-1, HeLa, SNU-C4, SK-MEL-28, and MDA-MB-231 human cancer cell lines. Additionally, all compounds were found to prevent EGF-induced neoplastic transformation of murine JB6 Cl41 cells. Nuclear factors AP-1, NF-κB, and p53 are involved in the cellular response to high and nontoxic concentrations of aaptamine alkaloids 1-3. Furthermore, inhibition of EGF-induced JB6 cell transformation, which is exerted by the compounds 1-3 at low nontoxic concentrations of 0.7-2.1 µM, cannot be explained by activation of AP-1 and NF-κB.

Quinone-carbohydrate nonglucoside conjugates as a new type of cytotoxic agents: synthesis and determination of in vitro activity.

We have found that 2-methoxy-1,4-naphthoquinones easily react with primary alcohols to produce the corresponding 2-alkoxyderivatives. Using this reaction, we synthesized methyl-6-O-(naphthalene-1,4-dione-2-yl)-α-D-glucopyranosides, a new type of water soluble quinone-carbohydrate nonglucoside conjugates. The resulting conjugates induced apoptosis in human cancer HeLa and normal mouse JB6 P(+) Cl41 cells with simultaneous inhibition of p53-dependant transcriptional activity, suggesting that the observed cell death was p53-independent. Furthermore, we analyzed structure-activity relationship and bioactivity of 2-hydroxy- and 2-methoxy-1,4-naphthoquinones as well as carbohydrate nonglucoside conjugates. All compounds containing a quinone moiety were able to inhibit p53-dependant transcriptional activity and exerted moderate inhibitory effects on HeLa cell colony formation. Investigations of structure-activity relationships revealed that cytotoxicity depended on the type of substituent at C-2 of the quinone moiety, decreasing in the following order: methoxyderivatives > carbohydrate nonglucoside conjugates > hydroxyderivatives. Furthermore, cytotoxicity depended on the position of the hydroxy substituent in the quinone moiety in all derivatives and decreased in the following order: 8- > 5- > 5,8-derivatives. In conclusion, this is the first report on synthesis and biological structure-activity relationships of the new class of quinone-carbohydrate nonglucoside conjugates.