7-O-氨基酸取代白杨素衍生物的合成及抗肿瘤活性

目的：设计并合成一系列白杨素衍生物,用MTT法测定化合物抗肿瘤活性,并研究其分子结构与分子对接的构效关系。方法：依次通过取代反应,水解反应,酯化反应,皂化反应等以高产率合成目标产物,并用人胃癌细胞系MGC-803和人乳腺癌细胞株MCF-7通过标准的MTT法测定化合物活性。用Sybyl X-2.0版的Surflex Geom X程序计算分子对接结果。结果：合成了7-O-氨基酸白杨素衍生物6a-6l,并通过与母体白杨素以及阳性对照药物5-氟尿嘧啶（5-FU）比较,评价其对肿瘤细胞的抑制作用。 在这些衍生物中,化合物5b（IC50 = 24.50 ± 2.26 μmol/L）,5k（IC50 = 24.30 ± 2.19 μmol/L）和6f（IC50 = 24.61 ± 2.01 μmol/L）对MGC-803细胞具有更好的抑制活性。化合物5g（IC50 = 13.15±1.73μmol/ L）和5j（IC50 = 12.34 ± 1.25 μmol/L）对MCF-7细胞的抑制活性优于白杨素和5-FU。 结合MTT实验结果,分子对接评分显示出可信的一致性。结论：化合物5b,5d,5g,5j,5k和6f对特定肿瘤细胞具有良好的抗增殖作用。结合分子对接实验,化合物5g值得进一步研究。

Synthesis and anti-tumor activities of novel 7-O-amino acids chrysin derivatives

Objective

To design and synthesize a series of chrysin derivatives and evaluate the antitumor activities with MTT assay, so as to investigate molecular structure-activity relationship with molecular docking.

Methods

Target products were synthesized with high yield by substitution reaction, hydrolysis reaction, esterification reaction, and saponification reaction in sequence, and activities of all compounds were evaluated with human gastric carcinoma cell lines MGC-803 and human breast carcinoma cell lines MCF-7 through standard MTT assay. Molecular docking results were calculated with Surflex Geom X programme of Sybyl X-2.0 version workstation.

Results

7-O-amino acids chrysin derivatives 6a–6l were synthesized and their inhibitory effects were evaluated by comparing the material chrysin with positive control drug 5-fluorouracil (5-FU). Among these derivatives, compound 5b (IC₅₀?=?24.50?±?2.26 µmol/L), 5k (IC₅₀?=?24.30?±?2.19 µmol/L), and 6f (IC₅₀?=?24.61?±?2.01 µmol/L) showed better inhibitory activities against MGC-803 cell lines, and compound 5g (IC₅₀?=?13.15?±?1.73 µmol/L) and 5j (IC₅₀?=?12.34?±?1.25 µmol/L) showed better inhibitory activities against MCF-7 cell lines than chrysin and 5-FU. Molecular docking scores showed a credible consistency compared with MTT results.

Conclusion

Compounds 5b, 5d, 5g, 5j, 5k, and 6f showed good antiproliferative effects on specific tumor cells, and compound 5g should be researched further when according to molecular docking.