【摘要】：小分子化合物作為釋藥系統(tǒng)早有研究,在本次研究中,我們?cè)谝延袑?shí)驗(yàn)結(jié)論的基礎(chǔ)上,對(duì)鄰硝基苯氧乙酸類(lèi)化合物腫瘤組織中的代謝設(shè)計(jì)及其作為釋藥系統(tǒng)做了初步評(píng)價(jià)。首先,合成得到化合物共16個(gè),并對(duì)苯氧乙酸類(lèi)化合物的熔點(diǎn)、溶解度、脂水分配系數(shù)、酸度系數(shù)進(jìn)行了測(cè)定,補(bǔ)充了這些化合物理化性質(zhì)數(shù)據(jù)的空白。然后,通過(guò)對(duì)比鄰硝基苯氧乙酸及其預(yù)期腫瘤代謝終產(chǎn)物2H-1,4苯并VA嗪-3(4H)-酮的抑菌活性、抗自由基活性、抗肝損傷活性、血管抑制活性,得知:鄰硝基苯氧乙酸和2H-1,4苯并VA嗪-3(4H)-酮對(duì)金黃色葡萄球菌和綠膿桿菌均具有抑制作用,前者傾向于抑制綠膿桿菌,后者傾向于抑制金黃色葡萄球菌;鄰硝基苯氧乙酸和2H-1,4苯并VA嗪-3(4H)-酮,均具有抑制羥基自由基的作用,后者明顯強(qiáng)于前者;鄰硝基苯氧乙酸對(duì)四氯化碳性L02損傷及酒精性L02損傷無(wú)保護(hù)作用,2H-1,4苯并VA嗪-3(4H)-酮對(duì)兩損傷具有保護(hù)作用;鄰硝基苯氧乙酸和H-1,4苯并VA嗪-3(4H)-酮均能通過(guò)抑制腫瘤細(xì)胞分泌促血管生長(zhǎng)因素控制腫瘤血管的生長(zhǎng),但鄰硝基苯氧乙酸抑制血管細(xì)胞接收生長(zhǎng)信號(hào),在抑制腫瘤血管生長(zhǎng)的同時(shí)可能影響正常血管細(xì)胞的生長(zhǎng),而苯并VA嗪-3(4H)-酮不影響血管細(xì)胞接收生長(zhǎng)信號(hào)。以上實(shí)驗(yàn)結(jié)論證明了針對(duì)鄰硝基苯氧乙酸在腫瘤中代謝為2H-1,4苯并VA嗪-3(4H)-酮的設(shè)計(jì)的合理性。最后,通過(guò)對(duì)氯硝基苯的硝基還原酶還原實(shí)驗(yàn)驗(yàn)證了苯環(huán)上硝基先還原為羥胺中間產(chǎn)物再還原為氨基的結(jié)論;通過(guò)檢測(cè)鄰硝基苯氧乙酸的硝基還原酶實(shí)驗(yàn)產(chǎn)物,探究了鄰硝基苯氧乙酸的還原過(guò)程,確定了鄰硝基苯氧乙酸5-氟尿嘧啶衍生物釋藥模型的兩條釋藥途徑;通過(guò)苯環(huán)上不同位置取代的鄰硝基苯氧乙酸硝基還原酶還原實(shí)驗(yàn),探究了鄰硝基苯氧乙酸苯環(huán)取代對(duì)硝基還原的影響,得到還原由易到難的順序?yàn)?4-氟鄰硝基苯氧乙酸(化合物1f)、5-氟鄰硝基苯氧乙酸(化合物1g)、鄰硝基苯氧乙酸(化合物1a)、4-甲基鄰硝基苯氧乙酸(化合物1c)、3-氟鄰硝基苯氧乙酸(化合物1e)、5-甲基鄰硝基苯氧乙酸(化合物1d)、3-甲基鄰硝基苯氧乙酸(化合物1b);通過(guò)酯鍵α位置不同取代的鄰硝基苯氧乙酸釋藥模型肝酶水解實(shí)驗(yàn),探究了釋藥模型酯鍵α位置取代對(duì)酯鍵水解的影響,得到水解由難到易的順序?yàn)?藥物模型酯鍵ɑ位引入兩個(gè)甲基、藥物模型酯鍵ɑ位引入一個(gè)乙基、藥物模型酯鍵ɑ位引入一個(gè)甲基;通過(guò)2-(4-氟-2-硝基苯氧基)-2-甲基丙酸-5-氟尿嘧啶甲酯與陽(yáng)性對(duì)照藥5-Fu的比較,得知前者抑制A549細(xì)胞增殖的能力雖不及5-Fu,但其大大降低了對(duì)WI-38的細(xì)胞毒性,對(duì)A549細(xì)胞增殖抑制的選擇性遠(yuǎn)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 偽 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 偽 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.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R914;R96

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