2-Amino-nonyl-6-methoxyl-tetralin muriate inhibits sterol C-14 reductase in the ergosterol biosynthetic pathway
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文摘
Aim: To investigate the action mechanism of a novel chemical structural aminotetralin derivate, 2-Amino-Nonyl-6-Methoxyl-Tetralin Muriate (10b), against Candida albicans (C albicans) in the ergosterol biosynthetic pathway.Methods: Antifungal susceptibility test of 10b was carried out using broth microdilution method, the action mechanism of 10b against C albicans was investigated by GC-MS spectrometry and real-time RT-PCR assay, and cytotoxicity of 10b in vitro was assessed by MTS/PMS reduction assay.Results: 10b reduced the ergosterol content markedly, and the 50% ergosterol content inhibitory concentration (ECIC_(50) value) was 0.08μg/mL.Although the sterol composition of 10b-grown cells was completely identical with that of erg24 strain, the content of ergosta-8,14,22-trienol in 10b-grown cells was much higher than that in erg24 strain. Real-time RT-PCR assay revealed a global upregulation of sterol metabolism genes. In addition, the 50% inhibitory concentration (IC_(50) value) of 10b was 11.30 μg/mL for murine embryonic fibroblasts and 35.70 μg/mL for human normal liver cells.Conclusion: 10b possessed a mode of action different from that of azoles and morpholines, whose targets were sterol C-14 reductase(encoded by ERG24 gene) and sterol C-5 desaturase (encoded by ERG3) related enzyme. Although 10b seemed to reduce MTS/PMS reduction in a dose dependent manner, IC_(50), value for mammalian cells was much higher than 50% minimum inhibitory concentration(MIC_(50)) value for C albicans. This indicates that the formulation is preliminarily safe and warrants further study for possible human applications.
来源
Acta Pharmacologica Sinica
,2009,30(12):1709-1716 【核心库】
DOI
10.1038/aps.2009.157
关键词
Candida albicans
;
sterol C-14 reducase
;
ergosterol
;
2-amino-nonyl-6-methoxyl-tetralin muriate
地址
1.
Department of Pharmacology,School of Pharmacy,Second Military Medical University, Shanghai, 200433
2.
Department of Pharmacy,General Hospital of Chengdu Military Command Region, Sichuan, Chengdu, 610083
3.
Department of Medicinal Chemistry,School of Pharmacy,Second Military Medical University, Shanghai, 200433
4.
Department of Pharmacology,School of Life Science and Biopharmacology,Shenyang Pharmaceutical University, Liaoning, Shenyang, 110016
5.
Department of Pharmacy,Beijing Stomatological Hospital,Capital Medical University, Beijing, 100050
语种
英文
文献类型
研究性论文
ISSN
1671-4083
学科
药学
基金
国家自然科学基金
文献收藏号
CSCD:3798143
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