二茂铁杂环类化合物的合成及抗三阴性乳腺癌活性研究

Synthesis of Ferrocenyl Heterocyclic Derivatives and Anti-triple Negative Breast Cancer Screening

关键词:  二茂铁衍生物  合成  抗三阴性乳腺癌

Key words:  ferrocenyl derivatives  synthesis  anti-triple negative breast cancer

摘要:

目的 设计、合成杂环二茂铁衍生物，并研究其抗三阴性乳腺癌活性。方法 以二茂铁查耳酮为先导化合物，对其进行结构改造，合成了一系列含有杂环的二茂铁衍生物，并通过CCK8试剂盒测试化合物抗乳腺癌活性。结果 合成了28个二茂铁衍生物，其结构均通过¹H-NMR和MS加以确证。初步的生物活性测试结果表明，所合成的二茂铁衍生物对三阴性乳腺癌MDA-MB-231细胞有较强的选择性和抑制活性，其中咪唑杂环化合物抗肿瘤活性强于相应的吡唑类和嘧啶化合物。尤其是28a[IC₅₀=（1.6±0.23）μmol·L^-1]对MDA-MB-231的抑制活性分别是先导化合物3[IC₅₀=（10.7±1.41）μmol·L^-1]和他莫昔芬[IC₅₀=（13.7±1.17）μmol·L^-1]的6和10倍，同时这些二茂铁衍生物对正常乳腺上皮细胞MCF-10A均没有毒性。结论 本研究为开发具有抗三阴性乳腺癌活性的化合物提供了信息和依据。

Abstract:

OBJECTIVE To design and synthesis of ferrocenyl heterocyclic derivatives and investigate anti-triple negative breast cancer activity. METHODS A series of ferrocenyl derivatives were designed and synthesized from ferrocenyl chalcone, and their anti-breast cancer activities were evaluated by CCK8 assay. RESULTS Twenty-eight ferrocenyl heterocyclic derivatives were synthesized and the structures had been confirmed by ¹H-NMR and MS spectra. The preliminary biological results showed that all synthesized ferrocenyl derivatives showed selective anticancer activity that were more potent against MDA-MB-231 cells than MCF-7, which also showed moderate inhibitory activity, against MDA-MB-231 cell lines, and imidazole heterocyclic compounds had more potent anti-tumor than corresponding pyrazole and pyrimidine derivatives, specifically, compound 28a[IC₅₀=(1.6±0.23)μmol·L^-1] showed about 6 and 10-fold potency than lead compound 3[IC₅₀=(10.7±1.41)μmol·L^-1] and tamoxifen[IC₅₀=(13.7±1.17)μmol·L^-1], against MDA-MB-231 cell lines, and these ferrocenyl derivatives were not toxic to normal cells. CONCLUSION This study provides information and basis for development of ferrocenyl derivatives with anti-triple negative breast cancer activity.