3,5(-E二)-亚苄基-N-环丙基哌啶-4-酮类化合物的合成及体外抗肿瘤活性研究

Synthesis and antitumor activity in vitro of 3,5-bis(substituted-benzylidene)-1-cyclopropylpiperidin-4-ones

目的合成3,5(-E二)-亚苄基-N-环丙基哌啶-4-酮类化合物,评价其体外抗肿瘤活性。方法以芳香醛、N-环丙基-4哌-啶酮为原料,通过C laisen-Sch im idt缩合反应制备3,5(-E二)-亚苄基-N-环丙基哌啶-4-酮类化合物。采用MTT法测试目标化合物对人慢性粒细胞白血病急变细胞K562、人急性髓细胞白血病细胞HL60、人结肠癌细胞SW 480、人结肠癌细胞SW 1116的抑制活性。结果与结论合成了12个未见文献报道的新化合物,目标化合物的结构经核磁共振氢谱和质谱确证。化合物1对HL60细胞的抑制活性比3,5-(E)-二(2-氟亚苄基)哌啶-4-酮醋酸盐(EF-24)强,化合物1和3对K562细胞的抑制活性比EF-24强,化合物2、6对SW1116细胞的抑制活性比EF-24强,所有目标化合物对SW480细胞的抑制活性均比EF-24弱。在EF-24的氮原子上引入环丙基或在苯环上引入强给电子取代基可增强化合物的抗肿瘤活性。

Curcumin,an active constituent of the herb Curcuma longa,was used to prevent and treat human tumor.In spite of being limited in vivo due to poor bioavailability,curcumin remains a good lead compound for futher drug design.3,5-Bis-（2-fluorobenzylidene）-piperidin-4-one（EF-24）as a curcumin analog was reported increased antitumor action in vitro and in vivo in comparison to curcumin.To optimize the antitumor activity of curcumin and EF-24,twelve 3,5-bis（benzylidene）-1-cyclopropylpiperidin-4-ones were designed by combination principles and bio-isosterism.These analogs were synthesized from aromatic aldehydes and 1-cyclopropyl-4-piperidone by Claisen-Schmidt condensation.Twelve analogs were unreported compounds and characterized by 1H-NMR and MS.Their in vitro antitumor activities were evaluated against four different tumor cell lines by MTT assay.The results showed that compound 1（IC50=6.84 μmol·L-1） and compound 3（7.51μmol·L-1） had much better activity against K562 cells than EF-24（IC50=8.88（μmol·L-1）.Compound 1（IC50=5.13 μmol·L-1） were more active than EF-24（IC50=11.2 μmol·L-1） in HL60,Compound 2（IC50=10.4 μmol·L-1） and compound 6（IC50=2.60 μmol·L-1） were stronger than EF-24（IC50=11.7 μmol·L-1） on SW1116.Most compounds showed weaker activity than EF-24（IC50=10.0 μmol·L-1） against SW480 cell line.These indicated that introduction of cyclopropyl at position 4-N of EF-24 could increase the cytotoxicity.In addition,strong electron-donating or halogen substitution on the benzene rings increased the cytotoxicity while strong electron-withdrawing or weak electron-donating group substitution decreased the cytotoxicity.