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2-Amino-nonyl-6-methoxyl-tetralin muriate inhibits sterol C-14 reductase in the ergosterol biosynthetic pathway.
- Source :
-
Acta pharmacologica Sinica [Acta Pharmacol Sin] 2009 Dec; Vol. 30 (12), pp. 1709-16. Date of Electronic Publication: 2009 Nov 16. - Publication Year :
- 2009
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Abstract
- 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.<br />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.<br />Results: 10b reduced the ergosterol content markedly, and the 50% ergosterol content inhibitory concentration (ECIC(50) value) was 0.08 microg/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 microg/mL for murine embryonic fibroblasts and 35.70 microg/mL for human normal liver cells.<br />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.
- Subjects :
- Animals
Antifungal Agents pharmacology
Azoles pharmacology
BALB 3T3 Cells drug effects
Biosynthetic Pathways
Hepatocytes drug effects
Humans
Inhibitory Concentration 50
Male
Mice
Microbial Sensitivity Tests
Oxidoreductases genetics
Up-Regulation
Candida albicans drug effects
Ergosterol metabolism
Oxidoreductases metabolism
Sterols metabolism
Tetrahydronaphthalenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1745-7254
- Volume :
- 30
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Acta pharmacologica Sinica
- Publication Type :
- Academic Journal
- Accession number :
- 19915585
- Full Text :
- https://doi.org/10.1038/aps.2009.157