title: Prenylated coumarins: natural phosphodiesterase-4 inhibitors from Toddalia asiatica.
abstract: Bioassay-guided fractionation of the ethanolic extract of the roots of Toddalia asiatica led to the isolation of seven new prenylated coumarins (1-7) and 14 known analogues (8-21). The structures of 1-7 were elucidated by spectroscopic analysis, and their absolute configurations were determined by combined chemical methods and chiral separation analysis. Compounds 1-5, named toddalin A, 3‴-O-demethyltoddalin A, and toddalins B-D, represent an unusual group of phenylpropenoic acid-coupled prenylated coumarins. Compounds 1-21 and four modified analogues, 10a, 11a, 13a, and 17a, were screened by using tritium-labeled adenosine 3',5'-cyclic monophosphate ([3H]-cAMP) as substrate for their inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds 3, 8, 10, 10a, 11, 11a, 12, 13, 17, and 21 exhibited inhibition with IC50 values less than 10 μM. Toddacoumalone (8), the most active compound (IC50=0.14 μM), was more active than the positive control, rolipram (IC50=0.59 μM). In addition, the structure-activity relationship and possible inhibitory mechanism of the active compounds are also discussed.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou, Guangdong 510006, People's Republic of China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Lin
authors.forename: Yi-You
authors.initials: YY
authors.lastname: Huang
authors.forename: Gui-Hua
authors.initials: GH
authors.lastname: Tang
authors.forename: Zhong-Bin
authors.initials: ZB
authors.lastname: Cheng
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
authors.forename: Sheng
authors.initials: S
authors.lastname: Yin
mesh_terms: D003374:Coumarins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D018517:Plant Roots / Q000737:chemistry; D020889:Rolipram / Q000494:pharmacology; D027821:Rutaceae / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D004365:Drugs, Chinese Herbal; D058988:Phosphodiesterase 4 Inhibitors; C000589781:toddalin A; D020889:Rolipram