Antiproliferative effect of synthetic cyclic imides (methylphtalimides, carboxylic acid phtalimides and itaconimides) against human cancer cell lines.

This work describes the antiproliferative potential of 14 cyclic imides (methylphtalimides, carboxylic acid phtalimides and itaconimides) against several human cancer cell lines. The antiproliferative effect was evaluated using the sulforhodamine B assay. Although some compounds from methylphtalimide and carboxylic acid phtalimide classes exhibited a selective antiproliferative activity, the itaconimides (11-14) exhibited the best results, especially compound 14, which presented a TGI (concentration that produces total growth inhibition) value of 0.0043 µM against glioma (U251), being inactive against the non-tumor cell line (HaCat). Absorption, distribution, metabolism and excretion in silico evaluations suggest that these compounds are promising candidates.

Antiproliferative effect of extracts and pyranonaphthoquinones obtained from Cipura paludosa bulbs.

CONTEXT: Cipura paludosa Aubl. (Iridaceae) is widely used in folk medicine to treat several ailments. Experimental studies have confirmed its anti-inflammatory, antinociceptive, and neuroprotective effects. OBJECTIVE: This study evaluates the possible antiproliferative potential of the crude methanol extract and three isolated compounds from the bulbs of C. paludosa. MATERIALS AND METHODS: Phytochemical analysis was carried out by conventional chromatographic techniques, and the resulting compounds were identified by NMR (1)H and (13)C. The antiproliferative activity was analysed using the sulforhodamine B assay. RESULTS: Crude methanol extract of C. paludosa bulbs showed GI50 values of between 1.6 and 30.8 µg/mL. The naphthoquinone derivatives (eleutherine, isoeleutherine, and eleutherol) isolated from the bulbs of C. paludosa exhibited promising cytotoxicity against several human tumour cell lines, especially the two main compounds, eleutherine and isoeleutherine, against glioma and breast cancer cell lines, with TGI values of between 2.6 and 13.8 µg/mL. CONCLUSION: Cipura paludosa bulbs produce active principles with relevant antiproliferative potential, such as naphthoquinone derivatives, identified as eleutherine, isoeleutherine, and eleutherol. This is the first report indicating C. paludosa with antiproliferative potential.

Synthesis of thiophene-thiosemicarbazone derivatives and evaluation of their in vitro and in vivo antitumor activities.

A series of thiophene-2-thiosemicarbazones derivatives (5-14) was synthesized, characterized and evaluated for their antitumor activity. They were tested in vitro against human tumor cell lines through the colorimetric method. The results revealed that compounds 7 and 9 were the most effective in inhibiting 50% of the cell growth after 48 h of treatment. As compound 7 showed a potent antiproliferative profile, it has been chosen for further studies in 786-0 cell line by flow cytometry. Treatments with compound 7 (50 µM) induced early phosphatidylserine exposure after 18 h of exposure and this process progressed phosphatidylserine exposure with loss of cell membrane integrity after 24 h of treatment, suggesting a time-dependent cell death process. Regarding the cell cycle profile, no changes were observed after treatment with compound 7 (25 µM), suggesting a mechanism of cell death independent on the cell cycle. The in vivo studies show that compound 7 possess low acute toxicity, being the doses of 30-300 mgKg(-1) chosen for studies in Ehrlich solid tumor model in mice. All doses were able to inhibit tumor development being the lowest one the most effective. Our findings highlight thiophene-2-thiosemicarbazones as a promising class of compounds for further studies concerning new anticancer therapies.

(-)-Tarchonanthuslactone: Design of New Analogues, Evaluation of their Antiproliferative Activity on Cancer Cell Lines, and Preliminary Mechanistic Studies.

Natural products containing the α,ß-unsaturated δ-lactone skeleton have been shown to possess a variety of biological activities. The natural product (-)-tarchonanthuslactone (1) possessing this privileged scaffold is a popular synthetic target, but its biological activity remains underexplored. Herein, the total syntheses of dihydropyran-2-ones modeled on the structure of 1 were undertaken. These compounds were obtained in overall yields of 17-21 % based on the Keck asymmetric allylation reaction and were evaluated in vitro against eight different cultured human tumor cell lines. We further conducted initial investigation into the mechanism of action of selected analogues. Dihydropyran-2-one 8 [(S,E)-(6-oxo-3,6-dihydro-2H-pyran-2-yl)methyl 3-(3,4-dihydroxyphenyl)acrylate], a simplified analogue of (-)-tarchonanthuslactone (1) bearing an additional electrophilic site and a catechol system, was the most cytotoxic and selective compound against six of the eight cancer cell lines analyzed, including the pancreatic cancer cell line. Preliminary studies on the mechanism of action of compound 8 on pancreatic cancer demonstrated that apoptotic cell death takes place mediated by an increase in the level of reactive oxygen species. It appears as though compound 8, possessing two Michael acceptors and a catechol system, may be a promising scaffold for the selective killing of cancer cells, and thus, it deserves further investigation to determine its potential for cancer therapy.

Two new hydronaphthoquinones from Sinningia aggregata (Gesneriaceae) and cytotoxic activity of aggregatin D.

Two new hydronaphthoquinones, aggregatins E and F (1 and 2, resp.) were isolated from the tubers of Sinningia aggregata (Ker-Gawl.) Wiehler (Gesneriaceae), along with twelve known compounds aggregatin D (3), tectoquinone (4), 1-hydroxy-2-methylanthraquinone (5), icosyl ferulate (6), pustuline (7), 1,6-dihydroxy-2-methylanthranquinone (8), 6-hydroxy-2-methylanthraquinone (9), 7-hydroxy-2-methylanthraquinone (10), tyrosol (11), halleridone (12), calceolarioside B (13), and cornoside (14). All compounds were identified by analysis of spectroscopic and spectrometric data. Compounds 3, 4, and 10 had already been reported in this species. Compounds 2 and 3 were evaluated against several tumor cell lines, but only 3 exhibited activities against UACC-62, 786-0 and OVCAR-3 cell lines, with IC50 values of 12.3, 12.8 and 0.3 µg/ml, respectively, without toxic effects on non-cancer cell line HaCat (human keratinocyte).