Labdane-type diterpenes from Hedychium gardnerianum with potent cytotoxicity against human small cell lung cancer cells.

Seven labdane-type diterpenes, coronarin E, coronarin A, yunnancoronarin A, yunnancoronarin B, hedyforrestin B, villosin, and hedyforrestin C were isolated from the rhizome of Hedychium gardnerianum and evaluated for cytotoxic activity against human small cell lung cancer (NCI-H187) and non-cancerous Vero cells. The results showed that villosin exhibited potent cytotoxic activity with IC(50) of 0.40 microM, which was higher than that of the drug ellipticine (IC(50) 1.79 microM). Moreover, ellipticine was very toxic to Vero cells (IC(50) 7.47 microM) whereas the toxicity of villosin was undetectable at concentration lower than 166.42 microM. The results have indicated that the lactone ring is essential for high cytotoxic activity and that the presence of a hydroxyl group at the 6 or 7 position causes decrease in activity. The very high cytotoxicity against the NCI-H187 cells and the exceptionally high selectivity index (>416) of villosin suggested that this compound may be used as a potential lead molecule for antitumor therapeutic development.

[Sanguinarine and ellipticine cytotoxic alkaloids isolated from well-known antitumor plants. Intracellular targets of their action]. / Sangvinarin i elliptitsin: tsitotoksicheskie alkaloidy, vydelennye iz izvestnykh protivoopukholevykh rastenil, i vnutrikletochnye misheni ikh delstviia.

Common molecular and cellular targets for alkaloids sanguinarine and ellipticine, isolated from well-known antitumor plants (as well as from their various natural and synthetic derivatives), have been studied and described. Sanguinarine and ellipticine are characterized by significant biological activities including a high antitumor potential. Among the important targets of their action the following are to be noted. 1. DNA and other double helical polynucleotides. Due to the ability of DNA-intercalation sanguinarine, ellipticine and some of their derivatives can modify the double helical structures and topological forms of polynucleotides. The results of these modifications in intercalative complexes manifest themselves in the inhibition of numerous enzymatic reactions, dependent on the structures and topological forms of DNA and other polynucleotides. 2. ATP synthesis in mitochondria. Most of DNA-intercalators, including sanguinarine and ellipticine, belong to a group of penetrating (hydrophobic) cations, which are accumulated near the external side of inner mitochondrial membranes during the membrane energization. They neutralize negative charges, arising just as the inner mitochondrial membranes become energized. By this neutralization of membrane charges the ATP synthesis in inhibited and the oxidative phosphorylation renders to be uncoupled. All studied DNA-intercalators under certain conditions uncouple the mitochondrial oxidative phosphorylation. Apparent correlation between the agents' ability for DNA-intercalation and for mitochondrial ATP synthesis inhibition seems to be determined by the importance for both types of reactions of molecule hydrophobicity and positive charges. 3. Cholinesterase systems. Sanguinarine, ellipticine and some of their derivatives, like other DNA-intercalators studied, inhibit also the enzymatic activities of cholinesterase systems due to hydrophobicity and positive charges of their molecules. 4. Sanguinarine (and chelerythrine), are also capable of inhibiting the biological activity of SH-dependent enzymes and proteins. Due to the reactivity of iminium groups in sanguinarine and chelerythrine molecules with nucleophilic reagents, e.g. thiol groups of enzymes and other proteins, the activities of SH-enzymes and proteins are inhibited. In particular, sanguinarine and chelerythrine inhibit enzymatic activity of some SH-dependent ATPases, including membrane-bound cation-transport ATPases. The earlier accumulated experience of the application in medicine of plant saps and extracts containing these alkaloids, and of the treatment of many diseases (including benign and malignant tumors) by isolated alkaloids may be explained, to a certain extent, by the inhibition of activities of the above mentioned cellular targets. The selective toxicity of these alkaloids for the number of transformed cells can be explained in the same manner.

Comparative in vitro and in vivo antimalarial activity of the indole alkaloids ellipticine, olivacine, cryptolepine and a synthetic cryptolepine analog.

Indole alkaloids ellipticine (1), cryptolepine triflate (2a), rationally designed 11-(4-piperidinamino)cryptolepine hydrogen dichloride (2b) and olivacine (3) (an isomer of 1) were evaluated in vitro against Plasmodium falciparum and in vivo in Plasmodium berghei-infected mice. 1-3 inhibited P. falciparum (IC50≤1.4 µM, order of activity: 2b>1>2a>3). In vitro toxicity to murine macrophages was evaluated and revealed selectivity indices (SI) of 10-12 for 2a and SI>2.8×10² for 1, 2b and 3. 1 administered orally at 50mg/kg/day was highly active against P. berghei (in vivo inhibition compared to untreated control (IVI)=100%, mean survival time (MST)>40 days, comparable activity to chloroquine control). 1 administered orally and subcutaneously was active at 10 mg/kg/day (IVI=70-77%; MST=27-29 days). 3 exhibited high oral activity at ≥50 mg/kg/day (IVI=90-97%, MST=23-27 days). Cryptolepine (2a) administered orally and subcutaneously exhibited moderate activity at 50mg/kg/day (IVI=43-63%, MST=24-25 days). At 50 mg/kg/day, 2b administered subcutaneously was lethal to infected mice (MST=3 days) and moderately active when administered orally (IVI=45-55%, MST=25 days). 1 and 3 are promising compounds for development of antimalarials.

[A new quaternary alkaloid from Aspidosperma gilbertii]. / Um novo alcalóide quaternário de Aspidosperma gilbertii.

The present work describes the structure determination of a new quaternary carbozol type alkaloid, isolated from Aspidosperma gilbertii: N,N-Dimethyltetrahydroellipticinium Hydroxyde.

New indole alkaloids from the roots of Ochrosia acuminata.

Two new indole alkaloids, polyneuridine-N-oxide (1) and 17-hydroxy-10-methoxy-yohimbane (2), together with seven known alkaloids were isolated from the roots of Ochrosia acuminata collected in Savu, Indonesia. 9-Methoxyellipticine (3) and ellipticine (4) were responsible for the antitumor activities of the extract. The structures of all compounds were elucidated using MS and NMR methods.