Prenylated Coumarins: Natural Phosphodiesterase‑4 Inhibitors from Toddalia asiatica

• Published in: Journal of natural products (Washington, D.C.) Vol. 77; no. 4; pp. 955 - 962
• Main Authors: Lin, Ting-Ting, Huang, Yi-You, Tang, Gui-Hua, Cheng, Zhong-Bin, Liu, Xin, Luo, Hai-Bin, Yin, Sheng
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society and American Society of Pharmacognosy 25.04.2014; Amer Chemical Soc
• Subjects: active ingredients; asthma; Chemistry, Medicinal; coumarins; Coumarins - chemistry; Coumarins - isolation & purification; Coumarins - pharmacology; cyclic AMP; drugs; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - isolation & purification; Drugs, Chinese Herbal - pharmacology; fractionation; Humans; inhibitory concentration 50; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pharmacology & Pharmacy; Phosphodiesterase 4 Inhibitors - chemistry; Phosphodiesterase 4 Inhibitors - isolation & purification; Phosphodiesterase 4 Inhibitors - pharmacology; plant extracts; Plant Roots - chemistry; Plant Sciences; Rolipram - pharmacology; roots; Rutaceae - chemistry; Science & Technology; spectral analysis; Structure-Activity Relationship; structure-activity relationships; tritium; RUTACEOUS PLANTS; T-ACULEATA PERS; CHEMICAL-CONSTITUENTS; ROOT; DIMER; MOLECULAR DOCKING; DERIVATIVES; BIOASSAY
• ISSN: 0163-3864; 1520-6025; 1520-6025
• DOI: 10.1021/np401040d

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.