川芎嗪查尔酮类化合物的合成及其体外抗乳腺癌活性研究

目的设计、合成川芎嗪查尔酮类化合物并研究其抗乳腺癌活性。方法以盐酸川芎嗪为原料,通过酸碱中和、单氧化、重排、水解和醇羟基氧化制得重要中间体3,5,6-三甲基吡嗪-2-甲醛,再与芳乙酮发生Claisen-Schmidt羟醛缩合反应合成川芎嗪查耳酮类化合物,接着用BBr_3进行脱甲基得到了川芎嗪羟基查耳酮,并采用MTT法对目标化合物进行体外抗乳腺癌活性研究。结果合成了21个川芎嗪查尔酮类化合物,其结构均通过~1H-NMR和MS确证。生物活性结果测试表明,目标化合物对乳腺癌MCF-7和MDA-MB-231细胞均有较强抑制活,并对MDA-MB-231细胞有更强的选择抑制。其中查尔酮单元为二茂铁的衍生物9t对MCF-7和MDA-MB-231展现出了最强的抑制活性;同时,这些川芎嗪查尔酮类化合物对正常乳腺上皮细胞MCF-10A均没有毒性。结论查尔酮是一个重要的抗肿瘤药效团,能够提高川芎嗪的抗肿瘤活性,为今后发展新型、高效、低毒的具有抗肿瘤活性的川芎嗪衍生物提供了新思路。

Synthesis of ligustrazine-chalcone derivatives and their anti-breast cancer activities in vitro

Objective To design and synthesis of ligustrazine-chalcone derivatives and investigate their anti-breast cancer activities in vitro. Methods Ligustrazine hydrochloride was used as starting material to synthesize the important intermediate 3, 5, 6-trimethylpyrazine-2-formaldehyde through acid base neutralization, monooxidation, rearrangement, hydrolysis and hydroxyl oxidation reaction. Ligustrazine-chalcone derivatives were obtained underwent Claisen-Schmidt Aldol condensation by treatment of intermediate 3, 5, 6-trimethylpyrazine-2-formaldehyde with aromatic acetone, then the methoxyl of ligustrazine-chalcone derivatives were converted into hydroxylated ligustrazine-chalcone derivatives through application of demethylating reagent BBr₃. The anti-breast cancer activities were determined by MTT assays. Results Twenty-one ligustrazine-chalcone derivatives were synthesized and the structures have been confirmed by ¹H-NMR and MS spectra. The biological results showed that all synthesized ligustrazine-chalcone derivatives showed selective anti-breast cancer activity that has more potent against MDA-MB-231 cells than MCF-7. Specifically, ferrocenyl ligustrazine-chalcone compound 9t exhibited the greatest potency against both MCF-7 and MDA-MB-231. Moreover, these ligustrazine-chalcone derivatives were not toxic to normal cells. Conclusion Chalcone unit is a kind of important anti-tumor pharmacophore, which can enhance the anti-tumor effect of ligustrazine, and this study provides a new idea for the development of new, high-efficient and low-toxic ligustrazine derivatives with anti-tumor activity.