全反式维甲酸—正丁酸、丙戊酸相结合的化合物的设计、合成及抗肿瘤活性研究

【作者】 王欣；

【导师】 赵临襄；

【作者基本信息】 沈阳药科大学 ， 药物化学， 2005， 硕士

【摘要】 全反式维甲酸(All-trans Retinoic Acid，ATRA)是维生素A的活性代谢产物，能够诱导急性早幼粒白血病(Acute Promyelocytic Leukemia，APL)细胞的分化，是临床上治疗APL的首选药物，具有完全缓解率高、毒副作用低等特点。近年来，组蛋白去乙酰酶(Histone Deacetylase，HDAC)抑制剂作为具有发展潜力的新型抗肿瘤药物引起了人们的重视。正丁酸和丙戊酸属于短链脂肪酸类HDAC抑制剂，它们通过去除组蛋白和转录基因上的乙酰基，上调组蛋白的乙酰化水平和p21，p53等转录基因的表达，具有抑制肿瘤细胞的增殖，诱导肿瘤细胞分化和／或凋亡的活性。正丁酸等HDAC抑制剂与ATRA联合使用，不仅能够增强ATRA对复发APL的活性，而且对ATRA不敏感型APL有效。应用前药理论，分别以乙二醇、对苯二酚、乙醇胺及乙二胺等为连结物，通过酯键和酰胺键将分化诱导剂ATRA与HDAC抑制剂正丁酸、丙戊酸连结起来，设计并合成了8个ATRA-正丁酸类化合物(XW-1～XW-8)和7个ATRA-丙戊酸类化合物(XL-1～XL-7)，均为未见文献报道的新化合物，其结构经~1H-NMR、MS和IR确证。采用避光反应、避光低压柱层析分离等措施，避免ATRA和目标化合物(XW，XL)的氧化和异构化，显著提高了收率。根据~1H-NMR，对目标化合物的全反式构型进行确证并初步总结了化合物的MS裂分规律。更多还原

【Abstract】 All-trans retinoic acid (ATRA) is a metabolite of vitamin A which is able to induce acute promyelocytic leukemia (APL) cells differentiation. It is used in clinic as an effective drug with high complete remission rate and limited side effects. In recent years, histone deacetylase (HDAC) inhibitors are emerging as potential anticancer agents. Butyric acid and valproic acid belong to short-chain fatty acid HDAC inhibitors. They can inhibit proliferation and induce differentiation and/or apoptosis of tumor cells by up-regulating histone acetylation and the expression of transcription factors, such as p21, p53. It has been proved that HDAC inhibitors, such as butyric acid, could increase the activities of ATRA in relapsed APL and ATRA-resistant APL when combined with ATRA.According to the prodrug theory, 15 compounds (XW-1～XW-8, XL-1～XL-7) have been designed and synthesized which connect ATRA and butyric acid, valproic acid with different linkers, such as glycol, hydroquinone, through ester or amide. These compounds are new compounds which structures have been characterized by the application of ~1H-NMR, MS and IR spectra.In order to preventing ATRA and compounds (XW, XL) from oxidation and isomerization, the reactions were stirred in the dark and the product was purified by flash chromatography in the dark. According to ~1H-NMR, the all-trans configurations of these 15 compounds were characterized and the characteristics of MS were summarized.更多还原