Exploration of essential structure of malloapelta B for the inhibitory activity against TNF induced NF-kappaB activation.
For the exploration of pharmacophoric moiety of malloapelta B (1) possessing the inhibitory activity of NF-kappaB activation, structural variation of alpha,beta-unsaturated carbonyl motif was attempted. 1 was reduced by catalytic hydrogenation, sodium borohydride, and lithium aluminumhydride. Catalytic hydrogenation with 30 psi or 15 psi of H2 gas of 1 generated 8-butyl-5,7-dimethoxy-2,2-dimethylchroman (2) and 1-(5,7-dimethoxy-2,2-dimethylchroman-8-yl)butan-1-one (3), respectively. Reduction with sodium borohydride occurred at the double bond of alpha,beta-unsaturated ketone of 1 to give 1-(5,7-dimethoxy-2,2-dimethyl-2H-chromen-8-yl)butan-1-one (4). Reduction of 1 with lithium aluminumhydride and then quenched with methanol and water produced unexpected products, 1-(5,7-dimethoxy-2,2-dimethyl-2H-chromen-8-yl)-3-methoxy-1-butene (5) and 1-(5,7-dimethoxy-2,2-dimethyl-2H-chromen-8-yl)-3-hydroxy-l-butene (6). These are formed from the isomerization of initial product 9 through the continuous conjugate carbocation intermediate 11. Addition of ethylmagnesium bromide and dimethyl malonate anion to 1 gave the conjugate adducts 7 and 8. Ethylmagesium bromide and sodium borohydride reduction unusually gave the conjugate addition due to steric congestion around carbonyl group of 1. Compound 2 exhibits the reduced inhibitory activity against NF-kappaB activation and the others do not show the activity. Therefore alpha,beta-unsaturated carbonyl group of 1 should be important for its inhibitory activity.
Van Luu
Chinh
C
Institute of Natural Products Chemistry, Vietnamese Academy of Science and Technology, Hanoi, Vietnam.
Van Chau
Minh
M
Lee
Jung-Joon
JJ
Jung
Sang-Hun
SH
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000737:chemistry* / Q000494:pharmacology*; D019665:Euphorbiaceae / Q000737:chemistry; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006865:Hydrogenation; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D015394:Molecular Structure; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013055:Spectrophotometry, Infrared / Q000379:methods; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D001578:Benzopyrans; D002839:Chromans; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C517306:malloapelta B; D000469:Alkaline Phosphatase