邻硝基芳酸衍生物抗肿瘤释药体系的可行性研究

发布时间：2018-11-24 16:01

【摘要】：小分子化合物作为释药系统早有研究,在本次研究中,我们在已有实验结论的基础上,对邻硝基苯氧乙酸类化合物肿瘤组织中的代谢设计及其作为释药系统做了初步评价。首先,合成得到化合物共16个,并对苯氧乙酸类化合物的熔点、溶解度、脂水分配系数、酸度系数进行了测定,补充了这些化合物理化性质数据的空白。然后,通过对比邻硝基苯氧乙酸及其预期肿瘤代谢终产物2H-1,4苯并VA嗪-3(4H)-酮的抑菌活性、抗自由基活性、抗肝损伤活性、血管抑制活性,得知:邻硝基苯氧乙酸和2H-1,4苯并VA嗪-3(4H)-酮对金黄色葡萄球菌和绿脓杆菌均具有抑制作用,前者倾向于抑制绿脓杆菌,后者倾向于抑制金黄色葡萄球菌;邻硝基苯氧乙酸和2H-1,4苯并VA嗪-3(4H)-酮,均具有抑制羟基自由基的作用,后者明显强于前者;邻硝基苯氧乙酸对四氯化碳性L02损伤及酒精性L02损伤无保护作用,2H-1,4苯并VA嗪-3(4H)-酮对两损伤具有保护作用;邻硝基苯氧乙酸和H-1,4苯并VA嗪-3(4H)-酮均能通过抑制肿瘤细胞分泌促血管生长因素控制肿瘤血管的生长,但邻硝基苯氧乙酸抑制血管细胞接收生长信号,在抑制肿瘤血管生长的同时可能影响正常血管细胞的生长,而苯并VA嗪-3(4H)-酮不影响血管细胞接收生长信号。以上实验结论证明了针对邻硝基苯氧乙酸在肿瘤中代谢为2H-1,4苯并VA嗪-3(4H)-酮的设计的合理性。最后,通过对氯硝基苯的硝基还原酶还原实验验证了苯环上硝基先还原为羟胺中间产物再还原为氨基的结论;通过检测邻硝基苯氧乙酸的硝基还原酶实验产物,探究了邻硝基苯氧乙酸的还原过程,确定了邻硝基苯氧乙酸5-氟尿嘧啶衍生物释药模型的两条释药途径;通过苯环上不同位置取代的邻硝基苯氧乙酸硝基还原酶还原实验,探究了邻硝基苯氧乙酸苯环取代对硝基还原的影响,得到还原由易到难的顺序为:4-氟邻硝基苯氧乙酸(化合物1f)、5-氟邻硝基苯氧乙酸(化合物1g)、邻硝基苯氧乙酸(化合物1a)、4-甲基邻硝基苯氧乙酸(化合物1c)、3-氟邻硝基苯氧乙酸(化合物1e)、5-甲基邻硝基苯氧乙酸(化合物1d)、3-甲基邻硝基苯氧乙酸(化合物1b);通过酯键α位置不同取代的邻硝基苯氧乙酸释药模型肝酶水解实验,探究了释药模型酯键α位置取代对酯键水解的影响,得到水解由难到易的顺序为:药物模型酯键ɑ位引入两个甲基、药物模型酯键ɑ位引入一个乙基、药物模型酯键ɑ位引入一个甲基;通过2-(4-氟-2-硝基苯氧基)-2-甲基丙酸-5-氟尿嘧啶甲酯与阳性对照药5-Fu的比较,得知前者抑制A549细胞增殖的能力虽不及5-Fu,但其大大降低了对WI-38的细胞毒性,对A549细胞增殖抑制的选择性远高于5-Fu。
[Abstract]:Small molecular compounds have long been studied as drug delivery systems. In this study, the metabolic design and drug delivery system of o-nitrophenoxyacetic acid compounds in tumor tissues were evaluated on the basis of previous experimental results. First of all, 16 compounds were synthesized, and the melting point, solubility, lipids water partition coefficient and acidity coefficient of phenoxyacetic acid compounds were determined, which supplemented the blank of the physical and chemical properties of these compounds. Then, the antimicrobial activity, free radical activity, anti-liver injury activity and vascular inhibition activity of o-nitrophenoxyacetic acid and its expected end product 2H-1- (4) benzo VA zizine-3 (4H) -one were studied. The results showed that o-nitro-phenoxyacetic acid and 2H-1- (4-benzo VA) -3 (4H) -one had inhibitory effects on both Staphylococcus aureus and Pseudomonas aeruginosa. The former tended to inhibit Pseudomonas aeruginosa and the latter tended to inhibit Staphylococcus aureus. Both o-nitro-phenoxyacetic acid and 2H-1- (4-benzoVA) -3 (4H) -ketone can inhibit hydroxyl radical, the latter is stronger than the former. O-nitrophenoxyacetic acid had no protective effect on carbon tetrachloride induced L02 injury and alcoholic L02 injury, but 2H-1C 4benzo VA zizine-3 (4H) -one had protective effect on both damage. Both o-nitro-phenoxyacetic acid and H-1- (4-benzo VA) -3 (4H) -ketone could control the growth of tumor blood vessels by inhibiting tumor cell secretion, but o-nitrophenoxyacetic acid could inhibit the growth signal of vascular cells. Inhibition of tumor angiogenesis may affect the growth of normal vascular cells, while Benzoxazine-3 (4H) -ketone does not affect the growth signal of vascular cells. The above results demonstrate the rationality of the design for the metabolism of o-nitrophenoxyacetic acid to 2H-1- (4H) -benzoxazine-3 (4H) -ketone in the tumor. Finally, the results of nitroreductase reduction of p-chloronitrobenzene proved that the nitro was first reduced to hydroxylamine intermediate product and then reduced to amino group in benzene ring. By detecting the nitroreductase products of o-nitrophenoxyacetic acid, the reduction process of o-nitrophenoxyacetic acid was investigated, and two release routes of 5-fluorouracil derivative of o-nitrophenoxyacetic acid were determined. In this paper, the effect of substituted phenoxyacetic acid ring on the reduction of p-nitrobenzene was studied through the reduction experiment of nitroreductase of o-nitrophenoxyacetic acid at different positions on benzene ring. The order of reduction from easy to difficult is: 4-fluoro-o-nitrophenoxyacetic acid (compound 1f), 5-fluoro-o-nitrophenoxyacetic acid (compound 1g), o-nitrophenoxyacetic acid (compound 1a), 4-methyl-o-nitrophenoxyacetic acid (compound 1c), 3-fluoro-o-nitrophenoxyacetic acid (compound 1e), 5-methyl-o-nitrophenoxyacetic acid (compound 1d), 3-methyl-o-nitrophenoxyacetic acid (compound 1b); In this paper, the effect of 伪 position substitution of ester bond on the hydrolysis of ester bond was studied by the experiment of enzymatic hydrolysis of ortho-nitrophenoxyacetic acid release model with different ester bond 伪 positions. The order of hydrolysis from difficult to easy is as follows: two methyl groups are introduced into the ester bond of drug model, one ethyl is introduced into the ester bond of drug model, and one methyl is introduced into the ester bond of drug model. By comparing 2- (4-fluoro-2-nitrophenoxy) -2-methylpropionic acid-5-fluorouracil (5-Fu) with 5-Fu, it was found that the former could not inhibit the proliferation of A549 cells. However, the cytotoxicity of A549 cells was significantly reduced, and the selectivity of inhibition on proliferation of A549 cells was much higher than that of 5-Fu.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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