色胺酮衍生物的设计合成及其抗肿瘤和抗菌活性研究

Design and synthesis of tryptanthrin derivatives as antitumor and antibacterial agents

目的设计合成一系列硝基取代的色胺酮(吲哚[2,1-b]喹唑啉-6,12-二酮)衍生物和D环取代衍生物,并进行初步体外抗肿瘤细胞增殖活性和抗菌活性研究。方法以吲哚醌(吲哚-2,3-二酮)衍生物和靛红酸酐(2H-苯并[d][1,3]噁嗪-2,4(1H)-二酮)衍生物为原料进行缩合反应得到色胺酮衍生物;通过MTT实验评价所合成化合物的体外抗肿瘤细胞增值活性;以滤纸片扩散法初步评价化合物的抗菌作用。结果8-硝基色胺酮(8-硝基-吲哚[2,1-b]喹唑啉-6,12-二酮)对肿瘤细胞A549和HCT116具有抑制增殖作用,对金黄色葡萄球菌Mu50、RN4220和Newman也具有抑制活性。化合物1k、1n对上述两种肿瘤细胞具有明显抑制作用,对金黄色葡萄球菌(Mu50、RN4220、Newman)也具有抑制活性。特别是1k对A549的增殖抑制强度(IC_(50)=3.58μmol·L^(-1))与阳性对照药吉非替尼相近,1b、1h、1k、1n对Mu50、RN4220、Newman的最小抑制浓度为0.63~1.25 mg·L^(-1),均小于阳性对照药物万古霉素(1.25~2.5 mg·L^(-1))。新化合物1d、1h、1j对A549细胞也表现出了较好的抑制活性,IC_(50)值分别为33.44、8.69、10.96μmol·L^(-1)。结论色胺酮2位硝基取代的衍生物减弱了母体的抗肿瘤和抗菌活性,而8位硝基取代增强了母体的抗肿瘤和抗菌活性。色胺酮D环7、8、9位引入氯、氟、溴原子时,能够提高母体的抗肿瘤和抗菌活性。

A series of nitrotryptanthrins(nitroindolo[2,1-b]quinazolin-6,12-dione)and D-ring substituted tryptanthrins(indolo[2,1-b]quinazolin-6,12-dione)were designed,prepared and their preliminary antiproliferative activities against tumor cell lines were evaluated using MTT assay and their antibacterial activities were screened using the disk diffusion method in vitro.The results indicated that 8-nitrotryptanthrin(nitroindolo[2,1-b]quinazolin-6,12-dione)exhibited good antitumor activity against A549 and HCT116,and also showed excellent antibacterial activity against three strains of Staphylococcus Mu50,RN4220 and Newman.Compounds 1k and 1n could inhibit the growth of two tumor cell lines and three strains of bacteria.Especially,1k showed similar inhibitory activities against A549 tumor cell line(IC_(50)=3.58μmol·L^(-1))compared with gefitinib and the minimum inhibitory concentration values of 1b,1h,1k and 1n against Staphylococcus Mu50,RN4220,Newman(MIC=0.63-1.25 mg·L^(-1))were lower than vancomycin(1.25-2.5 mg·L^(-1)).The new compounds 1d,1h and 1j also showed good inhibitory activities against A549 cell.with IC_(50)values of 33.44,8.69,and 10.96μumol·L^(-1),respectively.While 2-nitrotryptanthrin(2-nitroindolo[2.1-b]quinazolin-6,l2-dione)showed no significant antitumor and antibacterial activity.Furthermore,the results indicated that chlorine,fluorine and bromine atom substituted in the D-ring at the 7,8 and 9 position respectively enhanced the antitumor and antibacterial activity.