Novel naphtho[2,1-d]oxazole-4,5-diones as NQO1 substrates with improved aqueous solubility: Design,synthesis, and in vivo antitumor evaluation |
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Institution: | 1. Department of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA;2. Department of Radiation Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA;3. Department of Biochemistry, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA;4. Department of Pathology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA |
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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)naphtho2,1-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. |
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Keywords: | NQO1 substrates β-Lapachone Antitumor In vivo |
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