水溶性紫草素磺酸钠衍生物的设计合成及抗肿瘤活性

Synthesis of the bisulfite adducts of shikonin as water-soluble anticancer agents

目的为了解决抗肿瘤天然产物紫草素非选择性的细胞毒性,制备紫草素磺酸钠衍生物并测定其抗肿瘤活性及选择性,以寻找活性更好、毒性更低的先导化合物。方法以2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘为原料,经侧链羟基酯化、硝酸铈铵(CAN)氧化及共轭加成等4步反应,合成了水溶性的5,8-二甲基紫草素亚硫酸氢钠加成产物(目标物)。采用噻唑蓝(MTT)法测定目标化合物对人前列腺癌细胞DU145、人乳腺癌细胞M CF-7及人白血病细胞K562的生长抑制作用及选择性。结果与结论合成了8个未见文献报道的紫草素磺酸钠衍生物,其结构经1H-NM R、13C-NM R、HSQC及HM BC谱确证。M TT法测试结果表明,目标化合物对人白血病K562细胞具有一定的选择性,与先导物相比较,其水溶性得到明显改善。合成了新型紫草素磺酸钠衍生物,并初步分析了其构效关系,为紫草素类抗肿瘤新药的研究提供了理论依据。

Shikonin as a natural product from the radix of Lithospermum erythrorhizon Sieb. et. Zucc.,exhibited excellent anticancer effects. The naphthazarin moiety was recognized as its pharmacophore and was considered to be responsible for its pervasive toxicity,which was caused by the covalent binding of shikonin with cellular nucleophiles and the generation of reactive oxygen species（ ROS）. To a great extent,the pervasive toxicity of this hallmark molecule together with its poor water-solubility prevented the further development of shikonin towards clinics. In this study,eight bisulfite adducts of 5,8-dimethyl shikonin with caped naphthazarin scaffold were synthesized and evaluated for their anticancer activity against DU145,MCF-7 and K562 cells using the standard MTT assay. The synthetic routes included the esterification of the 1＇-hydroxyl group of 1,4,5,8-tetramethoxy-α-（ 3-methyl-2-buten-1-yl）-2-naphthalenemethanol,ammonium cerium（ Ⅳ）nitrate-mediated oxidation-demethylation and further conjugate addition of the quinones（ Ⅰ） with sodium bisulfite. The structures of the target compounds were elucidated by1H-NMR,13C-NMR,HSQC and HMBC spectra. The biological evaluation indicated that these newwater-soluble bisulfite adducts of shikonin（ Ⅲ andⅣ） exhibited selectivity towards K562 cell line and showed much better solubility than the lead compound.It will give us implications for the development of newshikonin derivatives as anticancer agents.