Novel naphtho[2,1-d]oxazole-4,5-diones as NQO1 substrates with improved aqueous solubility: Design, synthesis, and in vivo antitumor evaluation

详细信息    查看全文

• 作者：Xiang Li^a ; ^b ; ^&dagger ; ; Jinlei Bian^a ; ^&dagger ; ; Nan Wang^a ; Xue Qian^a ; Jing Gu^a ; Tong Mu^a ; Jun Fan^a ; Xiuwen Yang^a ; Shangzhen Li^a ; Tingting Yang^a ; Haopeng Sun^a ; ^c ; Qidong You^a ; ^{youqd@163.com" class="auth_mail" title="E-mail the corresponding author} ; Xiaojin Zhang^a ; ^c ; ^{zxj@cpu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：NQO1 substrates ; β-Lapachone ; Antitumor ; ortho-Naphthoquinones ; In vivo
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 March 2016
• 年：2016
• 卷：24
• 期：5
• 页码：1006-1013
• 全文大小：1488 K

文摘

A new series of ortho-naphthoquinone analogs of β-lapachone were designed, synthesized and evaluated. The biological results indicated that most of our compounds were efficient substrates for NQO1. The new scaffold with water-soluble side chain resulted in greater solubility under acidic condition compared to β-lapachone. Thus avoiding the use of hydroxylpropyl β-cyclodextrin which would finally cause the rapid drug clearance from the blood and dose-limiting toxicity in the form of hemolytic anemia. The most soluble and promising compound in this series was 2-((4-benzylpiperazin-1-yl)methyl)naphtho[2,1-d]oxazole-4,5-dione (3k), which inhibited cancer cell (NQO1-rich A549 cell line) growth at IC₅₀ values of 4.6 ± 1.0 μmol·L⁻¹. Furthermore, compound 3k had in vivo antitumor activity in an A549 tumor xenografts mouse model comparable to the activity obtained with β-lapachone. The results indicated that these ortho-naphthoquinones could serve as promising leads for further optimization as novel substrates for NQO1.