噻吩并[2,3-d]嘧啶类衍生物的合成及抗肿瘤活性

synthesis and antitumor activity of thieno[2,3-d]pyrimidine derivatives

摘要:

以2-丁酮、丙二腈和单质硫为原料，通过改良的Gewald反应合成2-氨基-3-氰基-4,5-二甲基噻吩，再与三氯氧磷和三氟乙酸反应“一锅法”合成关键中间体5,6-二甲基-2-三氟甲基-4-氯噻吩并[2,3-d]嘧啶，最后与取代苄胺发生取代反应制得16种噻吩并[2,3-d]嘧啶类含氟衍生物IIIa～IIIp。通过1HNMR、13CNMR、IR、MS和元素分析对目标化合物进行了表征，并经X射线单晶衍射测定了化合物IIIa的晶体结构。体外抗肿瘤活性结果表明，目标化合物IIIa、IIIc和IIIf表现出良好的抗肿瘤活性，苯环上被供电子基取代时目标化合物IIIk～IIIp的抗肿瘤活性均较差，苯环间位被吸电子基取代时活性较好（如IIIc、IIIf和IIIi），尤其是间位被氟原子取代时活性明显提高。化合物IIIa对MCF-7和HepG2细胞的半数抑制浓度（IC50）分别为2.01、2.44 μmol/L，IIIc对MCF-7和HepG2细胞的IC50分别为1.44、1.47 μmol/L，二者的活性均远优于对照组吉非替尼（Gefitinib）。

Abstract:

2-Amino-4,5-dimethylthiophene-3-carbonitrile was first obtained through the modified Gewald reaction with butan-2-one, malononitrile and elemental sulfur as raw materials. Then sixteen fluorinated thieno[2,3-d]pyrimidine derivatives IIIa~IIIp were synthesized by the substitution reaction of substituted benzylamines with the key intermediate 4-chloro-5,6-dimethyl-2-(trifluoromethyl)thieno[2,3-d]pyrimidine, which was prepared directly from 2-amino-4,5-dimethylthiophene-3-carbonitrile and trifluoroacetic acid in the presence of phosphorous oxychloride via one-pot procedure. The structures of these target compounds were confirmed by 1HNMR, 13CNMR, IR, MS and elemental analysis. The crystal structure of compound IIIa was determined by X-ray single-crystal diffraction. The bioassay results suggest that the target compounds IIIa, IIIc and IIIf exhibit good in vitro antitumor activity. The target compounds IIIk~IIIp with an electron-donating substituent in the benzene ring display poor antitumor activity, but the antitumor activity is better (e.g. IIIc, IIIf and IIIi) when the meta-position of the benzene ring was substituted with an electron-withdrawing group, especially a fluorine atom. The half inhibitory concentration (IC50) values of compound IIIa against MCF-7 and HepG2 cells were 2.01 μmol/L and 2.44 μmol/L, respectively, while the IC50 values of IIIc against MCF-7 and HepG2 cells were 1.44 μmol/L and 1.47 μmol/L, respectively. Both of them indicate much better antitumor activity than the control group Gefitinib.