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.
- 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: [email protected].
- 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: [email protected].
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.