title: 2-Amino-nonyl-6-methoxyl-tetralin muriate inhibits sterol C-14 reductase in the ergosterol biosynthetic pathway.
abstract: OBJECTIVE
  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 0.08 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Rong-mei
authors.initials: RM
authors.lastname: Liang
authors.forename: Yong-bing
authors.initials: YB
authors.lastname: Cao
authors.forename: Kai-hua
authors.initials: KH
authors.lastname: Fan
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.forename: Ping-hui
authors.initials: PH
authors.lastname: Gao
authors.forename: You-jun
authors.initials: YJ
authors.lastname: Zhou
authors.forename: Bao-di
authors.initials: BD
authors.lastname: Dai
authors.forename: Yong-hong
authors.initials: YH
authors.lastname: Tan
authors.forename: Shi-hua
authors.initials: SH
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.forename: Hong-tao
authors.initials: HT
authors.lastname: Liu
authors.forename: Yuan-ying
authors.initials: YY
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D041702:BALB 3T3 Cells / Q000187:drug effects; D053898:Biosynthetic Pathways; D002176:Candida albicans / Q000187:drug effects*; D004875:Ergosterol / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C550315:2-amino-nonyl-6-methoxyl-tetralin muriate; D000935:Antifungal Agents; D001393:Azoles; D013261:Sterols; D013764:Tetrahydronaphthalenes; D010088:Oxidoreductases; C039306:sterol delta-5 desaturase; C022672:delta(14)-sterol reductase; D004875:Ergosterol