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目的设计合成20个2,5(6)-双取代环戊(己)酮类化合物,进行抗肿瘤活性研究。方法以WB852为先导化合物,设计合成了20个2-取代胺甲基-5(6)-(E)-取代亚甲基环戊(己)酮盐酸盐类化合物。利用MTT法对其中17个化合物进行了体外细胞毒活性筛选,所用肿瘤细胞株为人乳腺癌细胞T47D、MCF-7、MCF-7/Adr;通过Habig的酶动力学方法,测试了部分目标化合物细胞外对GSTπ活性的影响。结果与结论合成了20个2-取代胺甲基-5(6)-(E)-取代亚甲基环戊(己)酮盐酸盐类化合物,其中16个为未见文献报道的新化合物,其结构均经1H-NMR、MS和IR确证。体外抗肿瘤活性筛选结果,17个化合物对3种肿瘤细胞均有不同程度的生长抑制活性,A-16、A-17、A-18、A-19等4个化合物活性显著,值得进行深入研究。9个化合物均有不同程度地抑制GSTπ的活性,其中A-4、8、9、11和15等5个化合物对GSTπ的抑制作用强于WB852。取代胺甲基部分、取代亚甲基侧链的改变以及环的大小对抗肿瘤活性和选择性影响不大,但显著影响对GSTπ的抑制作用。A-16、A-17、A-18、A-19对MCF-7/Adr的生长抑制作用与WB852相当,但均低于对MCF-7细胞的活性,对耐药细胞的活性与GSTπ抑制无关。
Objective To design and synthesize 20 2,5 (6) -disubstituted cyclopentanone compounds for antitumor activity. Methods Based on WB852 as the lead compound, 20 2-substituted aminomethyl-5 (6) - (E) -substituted methylenecyclopentanone hydrochlorides were designed and synthesized. Seventeen compounds were screened by MTT method in vitro. The tumor cell lines were T47D, MCF-7, and MCF-7 / Adr. Habig’s enzymokinetic method was used to test some of the target cells Effect of external on GSTπ activity. RESULTS AND CONCLUSION: Twenty compounds of 2-substituted aminomethyl-5 (6) - (E) -substituted methylenecyclopentanone hydrochloride were synthesized, of which 16 were new compounds not reported in the literature, Their structures were confirmed by 1H-NMR, MS and IR. The results of in vitro antitumor activity screening show that all 17 compounds have different degrees of growth inhibitory activity on the three kinds of tumor cells. Four compounds such as A-16, A-17, A-18 and A-19 have significant activity and deserve further study . All of the 9 compounds inhibited the activity of GSTπ to some extent. Among them, 5 compounds such as A-4, 8, 9, 11 and 15 inhibited GSTπ more than WB852. The substitution of the amine methyl moiety, the substitution of the methylene side chains, and the size of the ring have little effect on antitumor activity and selectivity but significantly inhibit the inhibition of GSTπ. The growth inhibitory effects of A-16, A-17, A-18 and A-19 on MCF-7 / Adr were similar to that of WB852 but lower than those on MCF-7 cells, Nothing to do