Terpene Conjugates of the Nigella sativa Seed-Oil Constituent Thymoquinone with Enhanced Efficacy in Cancer Cells
Terpene Conjugates of the Nigella sativa Seed-Oil Constituent Thymoquinone with Enhanced Efficacy in Cancer Cells
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DOI：
10.1002/cbdv.200900328
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发表时间：
2010-01-01
影响因子：
2.9
通讯作者：
Schobert, Rainer
中科院分区：
文献类型：
--
作者：
Effenberger, Katharina;Breyer, Sandra;Schobert, Rainer
百里醌（TQ; 1）是黑籽油的弱抗癌成分。在人HL-60白血病、518A2黑色素瘤、多药耐药的KB-V1/Vbl宫颈癌和MCF-7/Topo乳腺癌细胞以及非恶性人包皮成纤维细胞中测试了含有萜烯端6-烷基残基的衍生物。在醌和环单萜之间有短的四原子间隔的衍生物比具有较长间隔的类似物具有更强的抗增殖能力。6-（薄荷基-丁基）百里醌（3a）在所有四种细胞系中均表现出个位数的微摩尔IC50 （72 h）值。它在518A2黑色素瘤细胞中的活性是TQ(1)的7倍，在KB-V1/Vbl宫颈癌细胞中的活性是TQ(1)的4倍，而在成纤维细胞中的毒性仅为TQ(1)的一半。化合物3a也不是耐药癌细胞的P-gp和BCRP药物转运体的底物。石竹酚和大红基结合物3e和M特异性抑制耐药MCF-7乳腺癌细胞的生长。TQ与三萜白桦酸通过OH基团偶联导致活性丧失，而通过羧酸偶联使化合物4对HL-60细胞具有纳摩尔IC50（72小时）活性。TQ(1)的所有抗癌活性衍生物都能诱导细胞凋亡，并伴有DNA阶梯化、线粒体膜电位降低和活性氧的轻微增加。
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-(Menthoxy-butyryl)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 M 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.