臺灣博碩士論文加值系統

在之前對於2-phenyl-1,8-naphthyridine-4-one (2-PN) 衍生物的研究中發現，其在第五或第六位上有甲基取代的化合物，不但具有強力抑制微小管聚合作用，而且在體外試驗中對血癌(HL-60)、黑色素瘤(SF-MEL-5)、卵巢癌(OVCAR-3)、中樞神經系統癌(SF-295)、前列腺癌(PC-3)等，都具有卓越的細胞毒性。
2-phenyl-1,8-naphthyridine-4-ones主要是依照下列的步驟來進行合成：以substituted 2-aminopyridines (4,5) 和 substituted ethyl benzoylacetates (3) 在PPA的存在下，進行縮合反應合成相對應的pyridopyrimidinones (6,7)。這些產物接著在liquid paraffin中以350℃熱重排成相對應的2-PN。然而由於其低水溶性限制了2-PN在體內的效力。為了藉由增加水溶性來增進2-PN的生體可用率，我們把親水性基團引入2-PN的四位上形成5-methyl-2-(3-methoxyphenyl)-4-O-(β-D-glucopyranosyl)-1,8-naphthyridine (12) 和substituted 2-phenyl-1,8-naphthyridin-4-oxyalkylcarboxylic acid (17-24)來當作標的化合物。
各種2-PN第四位上具有親水性基團取代的化合物是否能增加其生體可用率的研究正在進行中。

In our previous studies of 2-phenyl-1,8-naphthyridine-4-one (2-PN) derivatives, compounds with a methyl group at the 5- or 6- position, were potent inhibitors of tubulin polymerization and showed remarkable cytoxicity in vitro against leukemia (HL-60), prostate cancer (PC-3), ovarian cancer (OVCAR-3), CNS cancer (SF-295) and melanoma (SF-MEL-5).
2-phenyl-1,8-naphthyridine-4-ones were synthesized according to following steps: condensation of substituted 2-aminopyridines (4,5) with substituted ethyl benzoylacetates (3) in the presence of polyphosphoric acid formed the corresponding pyridopyrimidinones (6,7). These kinetically favored products were then thermally converted at 350℃ in liquid paraffin to 2-PN (8,9). However, the low water-solubility of 2-PN limits its efficacy in vivo. In order to improve bioavailability by increasing solubility, we introduced hydrophilic group into the 4-position of 2-PN to form 5-methyl-2-(3-methoxyphenyl)-4-O-(β-D-glucopyranosyl)-1,8-naphthyridine (12) and substituted 2-phenyl-1,8-naphthyridin-4-oxyalkylcarboxylic acid (17-24) as target compounds.
Further pharmacokinetic investigation is underway to determine if hydrophilic substitution of the 4-position of 2-PNs will result in compounds with increased bioavailability.

英文摘要--5
中文摘要--6

第一章 序論
1.1 2-Phenyl-1,8-naphthyridin-4-one類緣化合物的合成方法及抗癌活性之研究概況--7
1.2 配醣體的吸收代謝及其合成方法之研究概況--13
1.3 研究目的與動機--18

第二章 結果與討論
2.1 2-Phenyl-1,8-naphthyridin-4-one之大量合成--20
2.1.1 3-Methoxy ethyl benzoylacetate (3)之合成--21
2.1.2 6, 7, 3''-Substituted phenylpyrido[1,2-a]pyrimidin-4-one(6, 7)之合成--22
2.1.3 5, 6, 3''-Substituted-2-phenyl-1,8-naphthyridin-4(1H)-ones (8, 9)之合成--26
2.1.4 重排反應與熱媒的探討--36
2.2 2-Phenyl-1,8-naphthyridin-4-one glucoside之合成--38
2.1.1 5-Methyl-2-(3-methoxyphenyl)-4-O-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1,8-naphthyridine (11)之合成--38
2.2.2 5-Methyl-2-(3-methoxyphenyl)-4-O-(β-D-glucopyranosyl)-1,8-naphthyridine (12)之合成--45
2.3 Substitued 2-phenyl-1,8-naphthyridin-4-oxyalkylcarboxylic acid之合成--50
2.3.1 Ethyl 4-oxo-substituted-2-(3-methoxyphenyl)-1,8-naphthyridin-4-yl acetate及butyrate(17-20)之合成--51
2.3.2 4-Oxo-substitued-2-(3-methoxyphenyl)-1,8-naphthyridin-4-yl acid (21-24)之合成--56

第三章 結論--59

第四章 實驗部分
4.1 試藥與溶媒--60
4.2 重要儀器--64
4.3 藥理試驗方法--66
4.4 化合物之製備--68
4.4.1 合成 3-Methoxy ethyl benzoylacetate--68
4.4.2 合成6- or 7-substituted-2-(3-methoxyphenyl)pyrido[1,2-a]pyrimidin-4-ones (6, 7)--69
4.4.3 合成5- or 6-methyl-2-(3-methoxyphenyl)-1,8-naphthyridin-4(1H)-ones (8, 9)--72
4.4.4 合成5-Methyl-2-(3-methoxyphenyl)-4-O-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1,8-naphthyridine(11)-76
4.4.5 合成5-Methyl-2-(3-methoxyphenyl)-4-O-(β-D-glucopyranosyl)-1,8-naphthyridine (12)--78
4.4.6 合成ethyl 4-oxo-6-methyl-2-(3-methoxyphenyl)-1,8-naphthyridin-4-yl acetate or butyrate (17-20)--80
4.4.7 合成4-oxo-substitued-2-(3-methoxyphenyl)-1,8-naphthyridin-4-yl-acid (21-24)--84

參考文獻--86

附錄--91

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