Four ardeemin analogs from endophytic Aspergillus fumigatus SPS-02 and their reversal effects on multidrug-resistant tumor cells.
Four ardeemin derivatives, 5-N-acetylardeemin (1), 5-N-acetyl-15bβ-hydroxyardeemin (2), 5-N-acetyl-15b-didehydroardeemin (3), and 5-N-acetyl-16α-hydroxyardeemin (4), were isolated from the fermentation broth of an endophytic Aspergillus fumigatus SPS-02 associated with Artemisia annua L. The structures of these metabolites were elucidated by a combination of spectroscopic data, including 1D-, 2D-NMR and MS. In vitro chemosensitization assay indicated that these ardeemins had different activities of reversing the multidrug-resistant (MDR) phenotype in three cancer cell lines, leukemia doxorubicin resistant cell K562/DOX, human lung adenocarcinoma cis-platin-resistant cell A549/DDP, and ovarian cancer cisplatin-resistant cell SK-OV-S/DDP. Compound 4 exhibited the strongest MDR reversing effect at 5 μM concentration in K562/DOX and A549/DDP cell lines 5.2±0.18-fold, 8.2±0.23-fold, respectively, while compound 2 had the highest reversal capacity in SK-OV-S/DDP cell line with 10.8±0.28 fold. Preliminary investigation of their structureactivity relationship suggested that a OH group at C(15b) or C(16) in ardeemin plays a key role in reversing the MDR effect. It is the first report on ardeemin analogs from endophytic A. fumigatus with reversal effects on MDR cancer cell lines K562/DOX, A549/DDP and SK-OV-S/DDP.
School of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. China (phone: +86-571-88320903; fax: +86-571-88320913). hwzhang@zjut.edu.cn.
Hua-Wei
HW
Zhang
Chen
C
Ying
Yi-Fei
YF
Tang
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D020014:K562 Cells; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D026121:Indole Alkaloids; C534892:ardeemin
Ardeemin; Aspergillus fumigatus; Endophytes; Multidrug resistance; Structureactivity relationship (SAR)