Sandra Breyer

Terpene conjugates of the Nigella sativa seed-oil constituent thymoquinone with enhanced efficacy in cancer cells.

Thymoquinone (TQ; 1) is a weak anticancer constituent of black seed oil. Derivatives bearing terpene‐terminated 6‐alkyl residues were tested in cells of human HL‐60 leukemia, 518A2 melanoma, multidrug‐resistant KB‐V1/Vbl cervix, and MCF‐7/Topo breast carcinomas, as well as in non‐malignant human foreskin fibroblasts. Derivatives with a short four‐atom spacer between quinone and cyclic monoterpene moieties were more antiproliferative than analogues with longer spacers. 6‐(Menthoxybutyryl)thymoquinone (3a) exhibited single‐digit micromolar IC50 (72 h) values in all four cell lines. It was seven times more active than TQ (1) in 518A2 melanoma cells and four times in KB‐V1/Vbl cervix carcinoma cells, while only half as toxic in the fibroblasts. Compound 3a was also not a substrate for the P‐gp and BCRP drug transporters of the resistant cancer cells. The caryophyllyl and germacryl conjugates 3e and 3f specifically inhibited the growth of the resistant MCF‐7 breast carcinoma cells. Conjugation of TQ with the triterpene betulinic acid via the OH group as in 3g led to a loss in activity, while conjugation via the carboxylic acid afforded compound 4 with nanomolar IC50 (72 h) activity against HL‐60 cells. All anticancer‐active derivatives of TQ (1) induced apoptosis associated with DNA laddering, a decrease in mitochondrial membrane potential and a slight increase in reactive oxygen species.

Modulation of doxorubicin activity in cancer cells by conjugation with fatty acyl and terpenyl hydrazones.

Doxorubicin N-acylhydrazones derived from saturated, unsaturated and terpene-terminated fatty acids were tested for anticancer activity in cells of human HL-60 leukaemia, 518A2 melanoma, MCF-7/Topo breast and KB-V1/Vbl cervix carcinomas. In the latter, the N-heptadecanoyl hydrazone was more cytotoxic than its unsaturated C18-fatty acyl analogues and even three times more than doxorubicin. The (menthoxycarbonyl)undecanoyl hydrazone was twice as active as doxorubicin in these multidrug resistant KB-V1/Vbl and in the 518A2 cells and also more efficacious in KB-V1 and MCF-7 cells that had been desensitised for doxorubicin. All hydrazones induced apoptosis albeit by slightly different mechanisms. While apoptosis induction by the menthoxymalonyl hydrazone was characterized by an upfront increase in caspase-8 activity, all other hydrazones elicited a hike in caspase-9 activity. Treatment of HL-60 and 518A2 cells with doxorubicin or its heptadecanoyl, linolenoyl, (menthoxycarbonyl)undecanoyl or menthoxymalonyl hydrazones also led to diverging increases of the ratio of bax to bcl-2 mRNA expression, of reactive oxygen species and of mitochondrial membrane damage.

Effects of thymoquinone-fatty acid conjugates on cancer cells.

More than the sum of its parts: The seeds of Nigella sativa have been a traditional herbal remedy for ailments such as asthma, diarrhea, and cancer. Their essential oil is rich in polyunsaturated fatty acids and thymoquinone. By linking them covalently, a tremendous boost in anticancer activity can be achieved in resistant tumor cells.

Synthesis, anticancer activity, and iron affinity of the Actinoplanes metabolite 7,8-dihydroxy-1-methylnaphtho[2,3-c]furan-4,9-dione

The first synthesis of 7,8-dihydroxy-1-methylnaphtho[2,3-c]furan-4,9-dione (1), an isofuranonaphthoquinone produced by an Actinoplanes strain is described. Lactone ring opening of 6-methylfuro[3,4-c]furan-1(3H)-one (4) with ortho-lithiated veratrole (3), oxidation of product alcohol 5, and Friedel-Crafts acylation of the resulting aroylcarboxylic acid 7 afforded the mono methyl ether 2 of the target compound. The latter was obtained by demethylation of 2 with BBr(3) in 14% overall yield. While mono ether 2 was distinctly more cytotoxic than catechol 1 against a panel of five cancer cell lines, only the latter showed a siderophore-like binding affinity for Fe(III) with a complex dissociation constant K(D) of approximately 10(-29) M(3) (pM = 25.9).

Cellular localisation of antitumoral 6-alkyl thymoquinones revealed by an alkyne-azide click reaction and the streptavidin-biotin system.

The subcellular distribution and accumulation of thymoquinone 1, a natural anticancer agent, has hitherto been unknown. We prepared 6‐(dec‐9‐ynyl)thymoquinone 3, an alkyne‐labelled derivative with anticancer activity similar to that of its parent compound 1. Alkyne 3 was seen, after a Huisgen‐type click reaction with 3‐azido‐7‐hydroxycoumarin, to accumulate in distinct compartments of the nuclei of PtK2 potoroo kidney cells, and in adjoining regions that were stained with an antibody specific for the Golgi apparatus. In contrast, a biotinlabelled thymoquinone 4 seemed to accumulate across the entire cell nucleus upon visualisation with streptavidin; but this was less easily traceable because of co‐staining of other structures such as mitochondria. In conclusion, for small drug‐like molecules, visualisation by alkyne–azide cycloaddition seems to be superior to conventional visualisation by the biotin–streptavidin system.