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目的设计合成α-硫辛酸衍生物,并测定其体外对肿瘤细胞的抑制活性。方法首先,以邻硝基氟苯为起始原料,经亲电取代和氧化反应合成抗肿瘤药替拉扎明,同时以色氨酸为起始物合成L-色氨酸甲酯盐酸盐;然后将替拉扎明和色氨酸甲酯盐酸盐分别与外消旋的或光学纯的硫辛酸进行酰胺缩合制得目标化合物。采用MTT法考察目标化合物对肿瘤细胞株ES-2、K562、PC-3、MDA-MB-231和A549的体外抑瘤活性。结果与结论合成了4个未见文献报道的新硫辛酸衍生物,其结构经1H-NMR、MS谱确证。目标化合物对实验的肿瘤细胞均具有一定的抑制活性,其中,化合物Ⅱ的活性最好,其IC50值在10μmol·L-1以内。
Objective To design and synthesize α-lipoic acid derivatives and determine their in vitro inhibitory activity on tumor cells. Methods Firstly, o-nitrofluorobenzene was used as starting material to synthesize antitumor drug tirapazamine by electrophilic substitution and oxidation reaction. At the same time, tryptophan was used as the starting material to synthesize L-tryptophan methyl ester hydrochloride ; Then, the target compound is obtained by amide condensation of tirapazamine and tryptophan methyl ester hydrochloride respectively with racemic or optically pure lipoic acid. The anti-tumor activity of the target compounds against tumor cell lines ES-2, K562, PC-3, MDA-MB-231 and A549 was investigated by MTT assay. RESULTS AND CONCLUSION Four novel lipoic acid derivatives were synthesized and their structures were confirmed by 1H-NMR and MS. The target compounds have certain inhibitory activity on the experimental tumor cells, of which compound II has the best IC50 value of less than 10 μmol·L-1.