2-羥基苯基-6-甲基-1,8-萘啶-4-酮及2-(3-甲氧基苯基)-6-甲基-1,8-萘啶-4-酮-8-N-氧化物的合成及細胞致毒活性

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Title:	2-羥基苯基-6-甲基-1,8-萘啶-4-酮及2-(3-甲氧基苯基)-6-甲基-1,8-萘啶-4-酮-8-N-氧化物的合成及細胞致毒活性 Synthesis and cytotoxicity of 2-(hydroxyphenyl)-6-methyl-1,8-naphthyridin-4-ones and 2-(3-methoxyphenyl)-6-methyl-1,8-naphthyridin-4-one-8-N-oxide
Authors:	廖志彰;Chih-Chang Liao
Contributors:	藥學院藥物化學研究所碩士班
Keywords:	1,8-萘啶;磷酸鹽前驅藥;8-氮-氧化物;1,8-naphthyridin;phosphate prodrug;8-N-oxide
Date:	2010
Issue Date:	2010-09-29 14:10:27 (UTC+8)
Abstract:	中文摘要過去本研究室合成2-(3-methoxyphenyl)-6-methyl-1,8-naphthyridin-4-one（LYF-5）並發現此化合物具有很強的cytotoxicity，由於其水溶性很低所以試圖合成4-phosphate prodrug ，但因安定性不佳，未能進一步的開發。於是在本研究中設計了hydroxy及8-N-oxide兩類標的化合物，（I）hydroy類化合物（IIa-IIc、IIIa、IVa、IVb）以及（II）N-oxide化合物（Va），首先以2-aminopyridine和benzoyl acetate分別置入PPA中，可得到相對應的化合物pyrido-pyrimidine（5a-5g）。再經由熱重排反應即可得到相對應的化合物naphthyridinones（6a-6e、IVb、6g），最後再將化合物naphthyridin-ones（6a-6e）分別經由HBr去甲基化後即可獲得相對應的hydroxy類衍生物（IIa-IIc、7d、IIIa、IVa、IVb、7g）。另一方面將LYF-5透過m-CPBA的氧化即可得到化合物2-(3-hydroxyphenyl)-6-methyl -1,8-naphthyridin-4-ones 8-N-oxide（Va）。將合成的hydroxy類化合物（IIa-IIc、7d、IIIa、IVa、IVb、7g）及化合物8-N-oxide（Va）分別與三個腫瘤細胞株及一個人類正常細胞株進行抗癌活性試驗的評估。對於上述三個腫瘤細胞測試的化合物，以2-(3-hydroxyphenyl) -6-methyl-1,8-naphthyridin-4-one（IIb）最具有發展潛力，並且對於正常細胞有很低的毒性。化合物IIb將進一步成為水溶性的磷酸衍生物，將可以提供動物試驗所需。 Abstract In the previous study, 2-(3-methoxyphenyl)-6-methyl-1,8-naphthyridin-4-one（LYF-5）was synthesized and found to possess strong cytotoxicity. Because of its low hydrophilicity, an attempt was made to synthesize of its 4-phosphate. Whereas the poor stability proinhibited it from further development . In this study, two kinds of target compounds, including hydroxyl derivatives（IIa-IIc、IIIa、IVa、IVb） and 8-N-oxide（Va）were designed. Condensation of 2-amiopyridine with benzoyl acetates in PPA formed the corresponding pyrido-pyrimidines（5a-5g）. Thermal rearrangement in mineral oil yielded the corresponding naphthyridinones（6a-6g）. Finally, these naphthyridin-ones（6a-6e）were demethylated separately with HBr to give the corresponding hydroxyl derivatives（7a-7f）. On the other hand, LYF-5 was oxidated by reacting with m-CPBA to 2-(3-methoxyphenyl)-6-methyl-1,8-naphthyridin-4-one 8-N-oxide（Va）. The synthesized hydroxyl drivatives（IIa-IIc、7d、IIIa、IVa、IVb）and 8-N-oxide compound（Va）were evaluated for their cytotoxicity against three cancer cell lines and human normal cell line. Among these tested compounds, 2-(3-hydroxyphenyl) -6-methyl-1,8-naphthyridin-4-one（IIb）exhibited promising cell growth inhibitory activity against three cancer cell lines with low cytotoxicity against human normal cell line. Compound that is IIb will be used as a parent molecule for preparing itswater solube phosphate that could be used for animal study.
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