Novel cytotoxic bufadienolides derived from bufalin by microbial hydroxylation and their structure-activity relationships.
Microbial transformation was used to prepare novel cytotoxic bufadienolides. Twelve products (3-14) were obtained from bufalin (1) by the fungus Mucor spinosus. Their structures were elucidated by high-resolution mass spectroscopy (HR-MS) and extensive NMR techniques, including 1H NMR, 13C NMR, DEPT, 1H-1H correlation spectroscopy (COSY), two dimensional nuclear Overhauser effect correlation spectroscopy (NOESY), heteronuclear multiple quantum coherence (HMQC), and heteronuclear multiple bond coherence (HMBC). Compounds 3, 4, 9 and 11-14 are new mono- or dihydroxylated derivatives of bufalin with novel oxyfunctionalities at C-1beta, C-7beta, C-11beta, C-12beta and C-16alpha positions. The in vitro cytotoxic activities against human cancer cell lines of 3-14, together with 16 biotransformed products derived from cinobufagin (15-30) were determined by the MTT method, and their structure-activity relationships (SAR) were discussed.
Ye
Min
M
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xueyuan Road #38, Beijing 100083, PR China.
Qu
Guiqin
G
Guo
Hongzhu
H
Guo
Dean
D
D001419:Bacteria / Q000378:metabolism; D001681:Biological Assay; D002018:Bufanolides / Q000737:chemistry*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004396:Coloring Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005658:Fungi / Q000378:metabolism; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008956:Models, Chemical; D010100:Oxygen / Q000737:chemistry; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014466:Ultraviolet Rays
D002018:Bufanolides; D004396:Coloring Agents; D004791:Enzyme Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; D010100:Oxygen; C022777:bufalin