2. Academic Validation
  3. Isolation and identification of phase I metabolites of butyrolactone I in rats

Isolation and identification of phase I metabolites of butyrolactone I in rats

  • Xenobiotica. 2017 Mar;47(3):236-244. doi: 10.3109/00498254.2016.1172280.
X An 1 2,  B-M Feng 3,  G Chen 1 2,  S-F Chen 1 2,  J Bai 1 2,  H-M Hua 1 2,  H-F Wang 1 2,  Y-H Pei 1 2
Affiliations

Affiliations

  • 1 a Key Laboratory of Structure-Based Drug Design & Discovery Ministry of Education , Shenyang Pharmaceutical University , Shenyang , China.
  • 2 b School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University , Shenyang , China , and.
  • 3 c School of Life Sciences and Biotechnology, Dalian University , Dalian , China.
PMID: 27604497 DOI: 10.3109/00498254.2016.1172280
Abstract

1. Butyrolactone I (BL-I), one of the major secondary metabolites of fungus Aspergillus terreus, is a selective cdc2 kinase inhibitor. In the present study, the metabolism of BL-I in male Wistar rats was investigated by characterizing metabolites excreted into feces. 2. Following an oral dose of 40 mg/kg BL-I, 10 phase I metabolites were isolated from the feces of rats, and their structures were identified on the basis of a range of spectroscopic data and ICD analysis. These metabolites were fully characterized as butyrolactone VI (M1), aspernolide E (M2), 7''S-hydroxy-9''-ene-butyrolactone I (M3), 7''R-hydroxy-9''-ene-butyrolactone I (M4), 7″S, 8″R-dihydroxy-aspernolide E (M5), 7″R, 8″S-dihydroxy-aspernolide E (M6), 7″R-acetyl-8″S-hydroxy-aspernolide E (M7), 7″S-acetyl-8″R-hydroxy-aspernolide E (M8), 7″R-methoxy-8″S-hydroxy-aspernolide E (M9), butyrolactone V (M10), respectively. It is the first time to describe the metabolites of BL-I in vivo, and metabolites M3 to M9 are new compounds. 3. BL-I and metabolites M2 to M10 were evaluated for their antimicrobial activity and in vitro antiproliferative activities. Only M-3 and M-4 showed inhibitory effect against staphylococcus aureus both with MIC of 125 μg/ml. BL-I and metabolites M-4 and M-5 exhibited potent Cancer cell growth inhibitory activities against HL-60 (human leukemia) cell lines with the IC50 values of 13.2, 28.8 and 35.7 μM, respectively. 4. On the basis of metabolites profile, a possible metabolism pathway for BL-I in rats has been proposed. This is the first systematic study on the phase I metabolites of BL-I.

Keywords

Butyrolactone I; cyclization; hydroxylation; metabolites.

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