کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1395521 1501126 2015 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Design and synthesis of new 2-arylnaphthyridin-4-ones as potent antitumor agents targeting tumorigenic cell lines
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Design and synthesis of new 2-arylnaphthyridin-4-ones as potent antitumor agents targeting tumorigenic cell lines
چکیده انگلیسی


• 2-Arylnaphthyridin-4-ones were synthesized as potent cytotoxic agents.
• 2-(3-Hydroxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (7a) was most potent.
• A phosphate prodrug (11) of 7a exhibited significant antitumor activity in vivo.
• Compound 11 has good development potential as an antitumor agent.

To develop new anticancer drug candidates from 2-arylnaphthyridin-4-one (AN), we have designed and synthesized a series of 3′-hydroxy and 6-hydroxy derivatives of AN. The results of cytotoxicity screening indicated that the replacement of the 3′-methoxy moiety on the C-ring phenyl group of AN (6a–e) with 3′-hydroxy (7a–e) made no significant effect on the inhibitory activity against HL-60, Hep3B and NCI-H460 cancer cell lines. On the other hand, replacing the 6-methoxy group on the A-ring of AN (6g–i) with a 6-hydroxy group (7g–i) resulted in reduced inhibitory activity against the above three cancer cell lines. Among the above-mentioned target compounds, 2-(3-hydroxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (7a) demonstrated the greatest potency and the best selectivity toward tumorigenic cancer cell lines. In a 7a preliminary mechanism of action study in Hep3B hepatoma cells, 7a showed the effects on microtubules followed by cell cycle arrest and sequentially led to apoptosis.In addition, a phosphate prodrug (11) of 7a exhibited significant antitumor activity when tested in a Hep3B xenograft nude mice model. Since compound 11 has demonstrated good development potential, it is recommended for further preclinical studies.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Medicinal Chemistry - Volume 90, 27 January 2015, Pages 775–787
نویسندگان
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