Terpene Conjugates of the Nigella sativa Seed‐Oil Constituent Thymoquinone with Enhanced Efficacy in Cancer Cells |
| |
Authors: | Katharina Effenberger Sandra Breyer Rainer Schobert |
| |
Institution: | Organisch‐chemisches Laboratorium der Universit?t Bayreuth, Universit?tsstra?e 30, NW 1, D‐95447 Bayreuth (fax: +49?(0)921?552671) |
| |
Abstract: | 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. |
| |
Keywords: | Terpene conjugates Nigella sativa Thymoquinone Anticancer activity |
|
|