Isolation and identification of phase I metabolites of butyrolactone I in rats.
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 IC50values 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.
a Key Laboratory of Structure-Based Drug Design & Discovery Ministry of Education , Shenyang Pharmaceutical University , Shenyang , China.|b School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University , Shenyang , China , and.
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X
An
c School of Life Sciences and Biotechnology, Dalian University , Dalian , China.
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Feng
a Key Laboratory of Structure-Based Drug Design & Discovery Ministry of Education , Shenyang Pharmaceutical University , Shenyang , China.|b School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University , Shenyang , China , and.
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Chen
a Key Laboratory of Structure-Based Drug Design & Discovery Ministry of Education , Shenyang Pharmaceutical University , Shenyang , China.|b School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University , Shenyang , China , and.
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Chen
a Key Laboratory of Structure-Based Drug Design & Discovery Ministry of Education , Shenyang Pharmaceutical University , Shenyang , China.|b School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University , Shenyang , China , and.
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Bai
a Key Laboratory of Structure-Based Drug Design & Discovery Ministry of Education , Shenyang Pharmaceutical University , Shenyang , China.|b School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University , Shenyang , China , and.
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Hua
a Key Laboratory of Structure-Based Drug Design & Discovery Ministry of Education , Shenyang Pharmaceutical University , Shenyang , China.|b School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University , Shenyang , China , and.
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HF
Wang
a Key Laboratory of Structure-Based Drug Design & Discovery Ministry of Education , Shenyang Pharmaceutical University , Shenyang , China.|b School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University , Shenyang , China , and.
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YH
Pei
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013211:Staphylococcus aureus
D000900:Anti-Bacterial Agents; C082868:butyrolactone I; D015107:4-Butyrolactone
Butyrolactone I; cyclization; hydroxylation; metabolites