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    Title: 2-(3-Substituted phenyl)-1,8-naphthyridin-4(1H)-one- 3-carboxylic Acid衍生物之合成及細胞致毒活性;Synthesis and Cytotoxicity Activity of 2-(3-Substituted phenyl)-1,8-naphthyridin-4(1H)-one-3-carboxylic Acid
    Authors: 林凱鵬;Kai-Peng Lin
    Contributors: 中國醫藥大學：藥物化學研究所碩士班
    Keywords: 細胞致毒活性;2-(3-Substituted phenyl)-1,8-naphthyridin-4(1H)-one-3-carboxylic Acid;Cytotoxicity
    Date: 2006-07-21
    Issue Date: 2009-08-13 09:37:28 (UTC+8)
    Abstract: 一系列2-phenyl-1,8-naphthyridin-4(1H)-one (2-PN)的衍生物已被合成出來，而且顯示其擁有很強的細胞致毒活性。然而對於臨床前試驗而言，這些化合物中大部分都有很大的親脂性和較差的藥物動力學性質。

    為了要改善2-PN衍生物在吸收、分佈、代謝、排泄方面的性質，著者設計並合成了一些3-carboxylic acid 的衍生物。將可購買到的3-substituted acetophenones 8-10分別和diethyl carbonate反應可得相對應的ethyl benzoylacetate 11-13。將適合的aminonicotinic acid和N-hydroxysuccinimide在以無水THF為溶媒，DCC的作用下得到醯化劑N-succinimide ester of aminonicotinic acid 6。再將化合物 11-13和醯化劑 6在以potassium t-butoxide為鹼的作用下，加熱至迴流溫度可環化縮合得2-PN衍生物14-16。最後用10% NaOH水溶液水解化合物 14-16可得標的化合物 17-19。著者以較溫和之反應條件成功地合成2-phenyl-1,8- naphthyridin-4(1H)-one-3-carboxylic acid之衍生物，提供作為藥物開發的方向。

    A series of 2-phenyl-1,8-naphthyridin-4(1H)-one (2-PN) derivatives has been synthesized and illustrated very potent cytotoxicity. However, most of them were quite lipophilic and poor pharmacokinetic characteristic for preclinical studies.
    In order to improve the ADME properties of 2-PNs, several 3-carboxylic acid derivatives were designed and synthesized. The appropriate ethyl benzoylacetate 11-13 were obtained from commercially available 3-substituted acetophenones 8-10 treated with diethyl carbonate, respectively. The acylating agent of N-succinimide ester of aminonicotinic acid 6 was prepared from appropriate aminonicotinic acid and N-hydroxysuccinimide in the presence of DCC in dry THF. To cyclocondensation of compounds 11-13 and acylating agent used potassium t-butoxide as a base at reflux afforded 2-PNs 14-16, respectively, bearing the 3-carboxyl moiety on the 3-position. Finally, the hydrolysis of compounds 14-16 by treatment with 10% NaOH(aq) gave target compounds 17-19, respectively. We provided successfully the synthetic route for the preparation of 2-phenyl-1,8-naphthyridin-4(1H)-one-
    3-carboxylic acid derivatives under smooth reaction conditions for drug development.
    Appears in Collections:[Graduate Institute of Pharmaceutical Chemistry] Theses & dissertations

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