title: Terpene conjugates of the Nigella sativa seed-oil constituent thymoquinone with enhanced efficacy in cancer cells.
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 IC(50) (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 IC(50) (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.
authors.affiliation: Organisch-chemisches Laboratorium der Universität Bayreuth, Universitätsstrasse 30, NW 1, D-95447 Bayreuth.
authors.forename: Katharina
authors.initials: K
authors.lastname: Effenberger
authors.forename: Sandra
authors.initials: S
authors.lastname: Breyer
authors.forename: Rainer
authors.initials: R
authors.lastname: Schobert
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D031881:Nigella sativa / Q000737:chemistry*; D009822:Oils, Volatile / Q000737:chemistry; D012639:Seeds / Q000737:chemistry; D013729:Terpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016227:Benzoquinones; D009822:Oils, Volatile; D013729:Terpenes; C003466:thymoquinone