含膦酸酯的L-苯丙氨酸二肽衍生物的合成及其抗肿瘤作用

Synthesis and antitumor activity of L-phenylalanine dipeptide derivatives containing phosphonate backbones

为了寻找抗肿瘤活性化合物,以芳香醛和亚磷酸二乙酯为原料,在三乙胺作用下,制备中间体Ⅰ;以L-苯丙氨酸甲酯盐酸盐和Boc-氨基酸为原料,经缩合、酯水解制备中间体Ⅱ;然后,中间体Ⅰ与中间体Ⅱ经1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐/1-羟基苯并三唑缩合,脱保护,制备了9个含膦酸酯结构的L-苯丙氨酸二肽衍生物,经^1HNMR、^13CNMR和MS对合成产物结构进行了确证。采用溴化噻唑蓝四氮唑(MTT)法对目标化合物进行了体外抗肿瘤活性测试。结果表明,部分目标物对所测肿瘤细胞有增殖抑制作用,呈现潜在的抗肿瘤活性。尤以O,O’-二乙基[α-(4-氟苯基)-α-(L-脯氨酰-L-苯丙氨酰氧基)]甲基膦酸酯(Ⅲi)最为突出,对人肺癌细胞(A-549)和人食管癌细胞(EC-109)均有显著抑制作用,对应的半抑制浓度(IC50)分别为(6.8±0.9)、(7.0±1.2)μmol/L,与对照药顺铂接近。

To search for antitumor compounds,intermediateⅠwas prepared from aromatic aldehydes and diethyl phosphite in the presence of triethylamine.IntermediateⅡwas obtained from L-phenylalanine methyl ester hydrochloride and Boc-amino acid by condensation and hydrolysis of ester.Then,nine L-phenylalanine dipeptide derivatives containing phosphonate backbones were synthesized from intermediateⅠand intermediateⅡby 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole condensation and deprotection.The structures of compounds were confirmed by 1 HNMR,13 CNMR and MS.These compounds were tested for their antitumor activities in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide(MTT)assay.The results showed that some of target compounds had inhibitory effect on the proliferation of the tumor cells and showed potential antitumor activity.Especially,O,O’-diethyl[α-(4-fluorphenyl)-α-(L-prolyl-L-phenylpropionyloxy)]methyl phosphonate(Ⅲi)showed remarkable activities against human lung cancer cell(A-549)and human esophageal cancer cells(EC-109).The corresponding half inhibition concentration(IC50)values were(6.8±0.9)and(7.0±1.2)μmol/L,respectively,which were close to those of cisplatin.