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.

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“…The protocols for expression, purification, and enzymatic assays of PDE4D2 were similar to those we described previously 31 . More details about the experimental procedures are provided in Supplementary S3.…”

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“…Enantiomeric mixtures 3 -5 were screened for inhibitory activity against PED4D2 according to the reported method. [35] and Xin Yu carried out the isolation and purification process. Dong-Mei Zhang and Hai-Bin Luo contributed to the biological activity assay.…”