Synthesis of hydrophilic derivatives of 5-Methyl-2-(3-methoxyphenyl)-1,8-naphthyridin-4-one

• Main Authors: Chin-Yu Liu, 劉晉育
• Other Authors: 郭盛助
• Format: Others
• Language: zh-TW
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/03648744475882260917

碩士 === 中國醫藥大學 === 藥物化學研究所碩士班 === 94 === 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.