大黄酸胺基醇酯衍生物的合成及其抗骨肉瘤细胞活性

Synthesis and biological evaluation of aminoalcohol rheinate as anti-osteosarcoma agents

以大黄酸为原料,设计、合成了24个大黄酸胺基醇酯衍生物。所合成的目标化合物均经IR、HR-MS及~1H NMR进行结构确认。水溶性测试实验表明,目标化合物的水溶性均有大幅提高,水中溶解度(10.04~15.08 mg·m L^(-1))是大黄酸(0.045 6 mg·m L^(-1))的220~330倍。采用MTT法对目标化合物进行了体外抗人骨肉瘤细胞U2OS活性测试,结果表明,所有目标化合物对人骨肉瘤细胞的抑制活性均显著高于大黄酸,大多数化合物的活性与临床常用抗骨肉瘤药物多柔比星相当,其中化合物4t抑制U2OS的活性最强,IC_(50)值为2.08μmol·L^(-1),略强于多柔比星。体外羟基磷灰石吸附实验表明,羟基磷灰石对4t的吸附值为13.97μmol·g^(-1),高于四环素(8.24μmol·g^(-1)),具有良好的骨靶向性。

Rhein （4,5-dihydroxyanthraquinone-2-carboxylic acid） is the primary anthraquinone in the roots of rhubarb. A recent study showed that rhein can inhibit tumor cell proliferation and induce apoptosis in human tumor cells. However, the clinical application of rhein has been hampered by its poor bioavailability, low aqueous solubility and gastrointestinal disorders. In current study, twenty-four target compounds were designed and synthesized by coupling various hydrophilic alkanolamines to the 2-carboxyl of rhein, and their structures were established by IR, HR-MS, 1H NMR spectra. Solubility test showed that all compounds were 10.04 to 15.08 mg·mL^-1 in water, which was 220 to 330-fold better than that of rhein （0.045 6 mg·mL^-1）. All of rhein derivatives displayed more potent anti-tumor activity than rhein, and most of them were comparable to adriamycin, particularly, compound 4t exhibited IC50 value of 2.08 μmol·L^-1, more effective than adriamycin （IC50=2.35 μmol·L^-1）. Hydroxyapatite adsorption experiment suggests that compound 4t has a better bone affinity than that of tetracycline.