2-取代胺甲基-5(6)-(E)-取代亚甲基环戊(己)酮盐酸盐类化合物的设计、合成及其抗肿瘤活性

Design,synthesis and antitumor activity of 2-alkylaminomethyl-5(6)-(E)-alkylmethylene(arylmethylene)-cyclopentanone(cyclohexanone) hydrochlorides

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 synthesis a series of 2,5 （ 6 ） -disubstituted cyclopentanones （ cyclohexanones）. Methods With WB852 as a lead compound, twenty systemically modified 2-alkylaminomethyl-5 （6） - （E） -alkylmethylene- （ arylmethylene ） -cyclopentanone （ cyclohexanone ） hydrochlorides were designed and synthesized. The in vitro antitumor activity of 17 compounds was conducted by using MTT assay in three breast cancer cell lines T47D ,MCF-7 and MCF-7/Adr cells. Using the Habig＇s method, some of target compounds were tested with the cell lysate of HL-60 cells as a GSTπ source. Results and Conclusion Twenty 2-alkylaminomethyl-5 （ 6 ） - （E） -alkylmethylene （ arylmethylene ） -cyclopentanone （ cyclohexanone ） hydrochlorides were designed and synthesized. Of the 20 target compounds, 16 are new compounds, whose chemical structures were characterized by the application of IR, MS and 1^H-NMR spectra. The screening of in vitro antitumor activity suggests that 17 compounds have different levels of growth inhibitory activities. Among these compounds, A-16, A-17 ,A-18, and A-19 show significant activity, and it is worth further study. Nine compounds have different degrees to inhibit the activity of the GSTπ, and the inhibition to GSTπ of A- 4,8,9,11, and 15 are stronger than WB852. Replace aminomethyl part,the change of replace methylene side chain and the ring size are little impact on anti-tumor activity and selectivity,but significant effect on GSTπ inhibition. A-16 ,A-17 ,A-18, A-19 which growth inhibition to MCF-7/Adr are equal to WB852, but show less of an effect on MCF-7, and the activity of resistant cells has nothing to do with GST-π inhibition.