Taspine:  Bioactivity-Guided Isolation and Molecular Ligand−Target Insight of a Potent Acetylcholinesterase Inhibitor fromMagnoliaxsoulangiana

Abstract

A bioactivity-guided approach was taken to identify the acetylcholinesterase (AChE, EC 3.1.1.7) inhibitory agent in a Magnolia x soulangiana extract using a microplate enzyme assay with Ellman's reagent. This permitted the isolation of the alkaloids taspine (1) and (−)-asimilobine (2), which were detected for the first time in this species. Compound 1 showed a significantly higher effect on AChE than the positive control galanthamine and selectively inhibited the enzyme in a long-lasting and concentration-dependent fashion with an IC 50 value of 0.33 ± 0.07 μM. Extensive molecular docking studies were performed with human and Torpedo californica-AChE employing Gold software to rationalize the binding interaction. The results suggested ligand 1 to bind in an alternative binding orientation when compared to galanthamine. While this is located in close vicinity to the catalytic amino acid triad, the 1-AChE complex was found to be stabilized by (i) sandwich-like π-stacking interactions between the planar aromatic ligand (1) and the Trp84 and Phe330 of the enzyme, (ii) an esteratic site anchoring with the amino side chain, and (iii) a hydrogen-bonding network.The enzyme acetylcholinesterase (AChE; EC 3.1.1.7) plays a central role in cholinergic brain synapses and neuromuscular junctions. Its major role is the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine (ACh). According to the cholinergic hypothesis, 1 the selective and irreversible deficiency of cholinergic functions leads to memory impairment. The direct correlation of cholinergic deficit and the severity of dementia, e.g., in patients suffering from Alzheimer's disease (AD) and other related diseases, is why these forms of memory impairment are treated symptomatically with AChE inhibitors (AChEIs). As knowledge of the mechanisms responsible for neurodegeneration in AD increases, it is anticipated that neuroprotective drugs will be developed to complement current symptomatic treatments. Research has shown a direct link between cholinergic impairment and altered amyloid precursor protein (APP) processing as a major pathogenetic

Antifungals and acetylcholinesterase inhibitors from the stem bark of Croton heliotropiifolius

“…(Vaisberg et al, 1989). Based on these results taspine could be one of the compound responsible for the AChE inhibition of the extract since it was already described as a strong inhibitor of AChE when investigated in a Magnolia species (Rollinger et al, 2006). Using the same procedure, 7 (m/z 359.2227 [M+H] + , C 22 H 31 O 4 (Dppm = 1.4)) was putatively identified as velamolone acetate, a diterpene previously described in Croton campestris A.…”

“…Taspine (4) has already been described for its AChE inhibitory properties (Rollinger et al, 2006); however, the activity of moschamine (5) is described here for the first time. This last compound was originally isolated from the seeds of Centaurea cyanus, a plant belonging to the Asteraceae family (Sarker et al, 1997).…”

Croton lechleri sap and isolated alkaloid taspine exhibit inhibition against human melanoma SK23 and colon cancer HT29 cell lines

“…(Magnoliaceae). Recently, interest is growing on the Croton lechleri sap and on its isolated alkaloid taspine (Fayad et al, 2009;Rollinger et al, 2006;Zhang et al, 2010).…”

Catechol alkenyls from Semecarpus anacardium: Acetylcholinesterase inhibition and binding mode predictions

“…At the active site, the ester bond of acetylcholine is hydrolyzed by the catalytic triad Ser200-His440-Glu327 ( Fig. 1) (Haviv et al, 2005;Rollinger et al, 2006).…”