A new family of choline kinase inhibitors with antiproliferative and antitumor activity derived from natural products

Background. Choline kinase alpha (ChoKα) is a critical enzyme in the synthesis of phosphatidylcholine, a major structural component of eukaryotic cell membranes. ChoKα is overexpressed in a large variety of tumor cells and has been proposed as a target for personalized medicine, both in cancer therapy and rheumatoid arthritis. Materials and methods. Triterpene quinone methides (TPQ) bioactive compounds isolated from plants of the Celastraceae family and a set of their semisynthetic derivatives were tested against the recombinant human ChoKα. Those found active as potent enzymatic inhibitors were tested in vitro for antiproliferative activity against HT29 colorectal adenocarcinoma cells, and one of the active compounds was tested for in vivo antitumoral activity in mice xenographs of HT29 cells. Results. Among 59 natural and semisynthetic TPQs tested in an ex vivo system, 14 were highly active as inhibitors of the enzyme ChoKα with IC50 <10 μM. Nine of these were potent antiproliferative agents (IC50 <10 μM) against tumor cells. At least one compound was identified as a new antitumoral drug based on its in vivo activity against xenographs of human HT-29 colon adenocarcinoma cells. Conclusions. The identification of a new family of natural and semisynthetic compounds with potent inhibitory activity against ChoKα and both in vitro antiproliferative and in vivo antitumoral activity supports further research on these inhibitors as potential anticancer agents. Their likely role as antiproliferative drugs deserves further studies in models of rheumatoid arthritis (AU)

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A new family of choline kinase inhibitors with antiproliferative and antitumor activity derived from natural products.

BACKGROUND: Choline kinase alpha (ChoKα) is a critical enzyme in the synthesis of phosphatidylcholine, a major structural component of eukaryotic cell membranes. ChoKα is overexpressed in a large variety of tumor cells and has been proposed as a target for personalized medicine, both in cancer therapy and rheumatoid arthritis. MATERIALS AND METHODS: Triterpene quinone methides (TPQ) bioactive compounds isolated from plants of the Celastraceae family and a set of their semisynthetic derivatives were tested against the recombinant human ChoKα. Those found active as potent enzymatic inhibitors were tested in vitro for antiproliferative activity against HT29 colorectal adenocarcinoma cells, and one of the active compounds was tested for in vivo antitumoral activity in mice xenographs of HT29 cells. RESULTS: Among 59 natural and semisynthetic TPQs tested in an ex vivo system, 14 were highly active as inhibitors of the enzyme ChoKα with IC50 <10 µM. Nine of these were potent antiproliferative agents (IC50 <10 µM) against tumor cells. At least one compound was identified as a new antitumoral drug based on its in vivo activity against xenographs of human HT-29 colon adenocarcinoma cells. CONCLUSIONS: The identification of a new family of natural and semisynthetic compounds with potent inhibitory activity against ChoKα and both in vitro antiproliferative and in vivo antitumoral activity supports further research on these inhibitors as potential anticancer agents. Their likely role as antiproliferative drugs deserves further studies in models of rheumatoid arthritis.

Acetylenic acids from the aerial parts of Nanodea muscosa.

The aerial parts of Nanodea muscosa, collected in Chile, yielded two new acetylenic acids. Their structures were elucidated by spectroscopic analyses, including 2D NMR techniques, as (13E)-octadec-13-en-11-ynoic acid (1) and (2E)-octadec-2-en-4-ynedioic acid (2). Compound 2 constitutes the first example of a conjugated ene-yne fatty diacid isolated from a natural source. Compounds 1 and 2 did not exhibit toxicity toward a panel of DNA damage checkpoint defective yeast mutants or show affinity for the 5-HT(1A), 5-HT(2A), D(2), and H(1) receptors.

Macrocarpins A-D, new cytotoxic nor-triterpenes from Maytenus macrocarpa.

Macrocarpins A (1), B (2), C (3) and D (4), four new nor-triterpenes, have been isolated from the roots of Maytenus macrocarpa. The structures were established by spectroscopic examinations. Natural compounds 1, 2, 4 and the acetyl derivative 1a are cytotoxic against four tumoral cell lines with IC50 values ranging between 0.4 and 5.2 microM.

Sesquiterpene polyol esters from the leaves of maytenus macrocarpa

The aerial parts of Maytenus macrocarpa yielded three new beta-dihydroagarofuran sesquiterpene polyol esters. Their structures were elucidated by spectroscopic analyses including 2D NMR techniques as 6beta,8beta,15-triacetoxy-1alpha, 9alpha-dibenzoyloxy-4beta-hydroxy-beta-dihydroagarofuran (1); 1alpha, 6beta,8beta, 15-tetraacetoxy-9alpha-benzoyloxy-4beta-hydroxy-beta-dihydroagarofura n (2) and (1S,4S,6R,7R,8R,9R)-1,6,15-triacetoxy-8, 9-dibenzoyloxy-4-hydroxy-beta-dihydroagarofuran (3). Compounds 1 and 2 showed marginal antitumor activity against four cell lines.

New phenolic and quinone-methide triterpenes from Maytenus amazonica.

The new nortriterpene methylene quinones amazoquinone (1) and (7S, 8S)-7-hydroxy-7,8-dihydro-tingenone (2), and the new norphenolic triterpenes 7,8-dihydro-6-oxo-tingenol (3), 23-nor-6-oxo-tingenol (4), and 23-oxo-iso-tingenone (5) were isolated from Maytenus amazonica. Their structures were elucidated by spectroscopic methods. Compounds 1, 2, 3, and 5 showed low antitumor activity against four cancer cell lines.

Friedelane triterpenoids from Maytenus macrocarpa.

A set of friedelane triterpenoids has been isolated from the stem bark exudates of Maytenus macrocarpa. It includes a new friedelan triterpene (1), together with the known compounds friedelin, 3-oxo-29-hydroxyfriedelane, 3-oxofriedelan-25-al, and canophyllol. The structures of these compounds were elucidated by spectroscopic and chemical evidence. Complete 1H and 13C assignments were achieved by 2D NMR spectroscopy. The new compound showed weak activity against aldose reductase. It did not display antitumor activity against P-388 lymphoid neoplasm, A-549 human lung carcinoma, HT-29 human colon carcinoma, or MEL-28 human melanoma cell lines.

Biological activities of some Argyranthemum species.

Seven species of the genus Argyranthemum were studied for antimicrobial and cytotoxic activities. Argyranthemum adauctum, A. foeniculaceum and A. frutescens showed antimicrobial activity against Gram-positive and Gram-negative and cytotoxic activity against HeLa and Hep-2 cell lines. Two new acetylenic compounds, frutescinol isovalerate and 3'-demethyl frutescinol isovalerate, were isolated from A. frutescens and their structures elucidated by spectroscopic studies.

Biological activity of secondary metabolites from Bupleurum salicifolium (Umbelliferae).

Secondary metabolites from Bupleurum salicifolium were tested against viruses, Gram-positive and Gram-negative bacteria, the yeast Candida albicans, the nematodes Globodera pallida and G. rostochiensis, the insect Spodoptera littoralis and the crustacean Artemia salina. These compounds were also tested against tumoral and non-tumoral cell lines. The polyacetylene 8S-heptadeca-2(Z)-9(Z)-diene-4,6-diyne-1,8-diol exhibited toxicity for A. salina and specific antibiotic activity against Gram-positive bacteria. Nine of the lignans and one coumarin showed toxicity for A. salina, and the lignans bursehernin and matairesinol inhibited the hatching of the two nematode species. These are the first lignans that have been reported as affecting phytoparasitic nematodes, and the first natural products known to have an effect on the hatching of G. pallida. Lignans may play a role in the defence mechanisms of potato plants, as allelopathic substances acting against cyst-forming nematodes.

Antibiotic activity and absolute configuation of 8S-heptadeca-2(Z),9(Z)-diene-4,6-diyne-1,8-diol from Bupleurum salicifolium.

A polyacetylene has been isolated from Bupleurum salicifolium. Its structure and absolute configuration were determined to be 8S-heptadeca-2(Z),9(Z)-diene-4,6-diyne-1,8-diol [1] by means of 1H- and 13C-nmr spectroscopic studies, including 1H-13C heteronuclear correlation (HMQC) and long-range correlation spectra with inverse detection (HMBC). Its absolute configuration was determined by application of the Horeau method. This compound exhibited significant antibiotic activity against the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis. Also isolated during this investigation were the known compounds; betulin, herniarin, 6,7,8-trimethoxycoumarin, p-hydroxyphenethyl alcohol, pluviatolide, guamaroline, bursehernin, guayadequiol, kaerophyllin, and matairesinol dimethyl ether.

Inhibition of potato cyst nematode hatch by lignans fromBupleurum salicifolium (Unbelliferae).

A series of lignans fromBupleurum salicifolium Soland (Umbelliferae) were tested for nematostatic activity on the cysts and freed secondstage juveniles of the potato cyst nematodesGlobodera rostochiensis andG. pallida. None of the six lignans tested-bursehernin, matairesinol, syringaresinol, the novel product buplerol, guayarol, and a derivative, nortrachelogenin triacetate-showed nematicidal activity in an in vitro analysis with second-stage juveniles, but significant differences were noted when the lignans were assayed for nematostatic activity as cyst hatching inhibitors. Bursehernin and matairesinol showed the greatest activity, at concentrations of 50 ppm. This is the first known instance of a natural product inhibiting the hatch of the nematodeG. pallida. The HID (hatching inhibiting dose) of bursehernin was estimated, and some conclusions were drawn about the structure-activity relationships of the lignans under study.