二茂铁异羟肟酸类组蛋白去乙酰化酶抑制剂的合成及其抗乳腺癌活性研究

Synthesis of ferrocenyl hydroxamic acid derivatives as histone deacetylases inhibitors and anti-breast cancer screening

目的设计、合成具有抗乳腺癌包括荷尔蒙依赖型(ER+)和非荷尔蒙依赖型(ER-)活性的二茂铁-组蛋白去乙酰化酶抑制剂(HDACi)缀合物。方法将二茂铁取代伏立诺他(SAHA)的一个苯环得到二茂铁-HDACi缀合物,测试这些化合物对HDAC1、6、8的抑制活性,并通过MTT法测试化合物的抗乳腺癌活性。结果合成了9个二茂铁-SAHA缀合物,结构均通过~1H NMR和^(13)C NMR进行了表征。初步的生物活性结果表明,这些二茂铁-HDACi缀合物对HDAC1、6、8均有较强的抑制作用,其中肟酸化合物(5a^5c)对HDAC1、6、8的抑制活性强于羧酸(4a^4c)和噻吩肟酸化合物(6a^6c)。在细胞抑制试验中,大部分二茂铁-HDACi缀合物对乳腺癌MCF-7和MDA-MB-231细胞具有较强的抑制活性,而对前列腺癌PC-3细胞的抑制活性较弱。此外,这些二茂铁-HDACi缀合物对正常VERO细胞没有毒性,而SAHA和他莫昔芬却有毒性。结论本研究为开发具有抗乳腺癌包括荷尔蒙依赖型(ER+)和非荷尔蒙依赖型(ER-)活性的药物提供了参考。

Objective To synthetize the ferrocene-HDACi conjugates with inhibitory activity in hormonedependent（ ER＋） and hormone-independent（ ER-） breast cancer cell lines. Methods One of the phenol ring in SAHA scaffold was substituted with ferrocenyl group to get ferrocene-HDACi conjugates,which were evaluated on HDAC1,6,8 inhibition activity,and the anti-breast cancer activity was assessed by MTT.Results Nine ferrocene-HDACi conjugates were synthesized,and these compounds had been confirmed by^1 H NMR and^（13） C NMR spectra. The preliminary biological results showed that these conjugates strongly inhibited HDAC1,HDAC6,HDAC8,and hydroxamic acid derivatives（ 5a- 5c） demonstrated high activity for HDAC1,HDAC6,HDAC8 over carboxylic acid（ 4a-4c） and thiohydroxamic acid（ 6a-6c） analogues.In cell proliferation assays,it was found that ferrocene-HDACi conjugates showed not only inhibition effect in hormone-dependent breast cancer MCF-7 cells but also in hormone-independent MDA-MB-231 cells,which had weak inhibitory activity on PC-3 cells. All conjugates were nontoxic to health VERO cells,while SAHA and tamoxifen showed essential toxicity. Conclusion This study provides information for development of drugs with inhibitory activity in hormone-dependent and hormone-independent breast cancer.