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

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

  • Bioorg Med Chem. 2016 Mar 1;24(5):1006-13. doi: 10.1016/j.bmc.2016.01.024.
Xiang Li 1,  Jinlei Bian 2,  Nan Wang 2,  Xue Qian 2,  Jing Gu 2,  Tong Mu 2,  Jun Fan 2,  Xiuwen Yang 2,  Shangzhen Li 2,  Tingting Yang 2,  Haopeng Sun 3,  Qidong You 4,  Xiaojin Zhang 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqd@163.com.
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zxj@cpu.edu.cn.
PMID: 26803578 DOI: 10.1016/j.bmc.2016.01.024
Abstract

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±1.0μmol·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.

Keywords

Antitumor; In vivo; NQO1 substrates; ortho-Naphthoquinones; β-Lapachone.

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