芳香烷胺类化合物的合成及体外抗肿瘤活性

Synthesis and in vitro Antitumor Activity of Aromatic Alkylamine Compounds

以二苯乙酸和4,4-二(4-氟苯)氯丁烷为原料,经过一系列偶联反应得到系列芳香烷胺类化合物(Ⅰ~Ⅶ),化合物的结构经~1HNMR,^(13)CNMR,MS确证。以化合物Ⅰ为例,对催化剂种类和用量,以及反应温度进行了优化。最佳合成条件为:4-二甲氨基吡啶(DMAP)为催化剂,n(DMAP)∶n[(S)-1-苯乙胺(3a)]=2∶1,反应温度为室温,在此条件下,化合物Ⅰ的收率为86.8%。采用MTT法选用人类前列腺癌细胞(DU145、PC3),乳腺癌细胞(MCF-7、MDB-MB-231、MDB-MB-453)和正常上皮细胞株(926)进行体外抗肿瘤活性测试。体外生物活性评价结果显示,化合物Ⅲ和Ⅳ具有良好的抗肿瘤生物活性,其中,化合物Ⅲ对MDB-MB-231,化合物Ⅳ对MDB-MB-453的抗肿瘤活性最佳[IC_(50)(半抑制浓度)分别为17.38,19.07μmol/L],但二者对正常上皮细胞杀伤效力较大(IC_(50)分别为19.20,26.37μmol/L)。化合物Ⅶ有一定的抗乳腺癌作用(对MCF-7、MDB-MB-231、MDB-MB-453的IC_(50)分别为52.03,49.74,30.09μmol/L),且对正常上皮细胞的IC_(50)>50μmol/L。

A series of novel aromatic alkylamine compounds were designed and prepared through coupling reaction using 1,1＇-（4-chlorobutylidene）bis（4-flourobenzene）and dibenzoic acid as raw materials.These compounds were characterized by^1HNMR,^（13）CNMR and MS.And the reaction conditions for the synthesis of compoundⅠwere optimized.The optimum reaction conditions were obtained as follows：When4-dimethylaminopyridine（DMAP）was used as catalyst,n（DMAP）∶n（3a）=2∶1 and reaction temperature was room temperature,the yield of compoundⅠreached 86.8%.In vitro antitumor activity of the compounds in human prostate cancer cell lines（DU145 and PC3）,breast cancer cell lines（MCF-7,MDB-MB-231 and MDB-MB-453）and normal epithelial cell line（926）were evaluated by MTT assay.The results indicated that compoundsⅢandⅣdisplayed excellent biological activities.CompoundⅢshowed an IC（50）of 17.38μmol/L against MDB-MB-231,and compoundⅣexhibited an IC（50）of 19.07μmol/L against MDB-MB-453.However,compoundsⅢandⅣshowed high toxicity on normal epithelial cell line（926）,and the IC（50）values were 19.20 and 26.37μmol/L,respectively.CompoundⅦhad certain inhibitory effect against breast cancer cell lines,the IC（50）values of compoundⅦagainst MCF-7,MDB-MB-231 and MDB-MB-453 were 52.03,49.74 and 30.09μmol/L.Furthermore,compoundⅦhad a low toxicity on normal epithelial cell line（926）with an IC（50）greater than 50μmol/L.