Xiao-Bing Wang

Design, synthesis, and acetylcholinesterase inhibitory activity of novel coumarin analogues.

Three series (series A-C) of coumarin analogues with phenylpiperazine functions as substitution were designed and synthesized for studying their potential for treating Alzheimers (AD) disease. Their anticholinesterase activities were assayed according to Ellmanns method against freshly prepared acetylcholinesterase (AChE) from Electrophorus electricus using donepezil as the reference compound. Pharmacological study and preliminary structure-activity relationships showed that coumarins with substitution on positions 3 and/or 4 have parallel anti-AchE activities compared with the reference compound.

Design, synthesis and evaluation of novel tacrine–coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer's disease

A series of tacrine-coumarin hybrids (8a-t) were designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimers disease (AD). The screening results showed that most of them exhibited a significant ability to inhibit ChE and self-induced β-amyloid (Aβ) aggregation, and to act as metal chelators. Especially, 8f displayed the greatest ability to inhibit acetylcholinesterase (AChE, IC50 = 0.092 μM) and Aβ aggregation (67.8%, 20 μM). It was also a good butyrylcholinesterase inhibitor (BuChE, IC50 = 0.234 μM) and metal chelator. Besides, kinetic and molecular modeling studies indicated that 8f was a mixed-type inhibitor, binding simultaneously to active, peripheral and mid-gorge sites of AChE. These results suggested that 8f might be an excellent multifunctional agent for AD treatment.

Design, synthesis and biological evaluation of imine resveratrol derivatives as multi-targeted agents against Alzheimer's disease

A series of imine resveratrol derivatives (1-20) have been designed, synthesized, and evaluated as multi-targeted compounds for the treatment of Alzheimers disease (AD). In vitro studies show that most of the molecules exhibit a significant ability to inhibit self-induced and Cu(2+)-induced β-amyloid (Aβ₁₋₄₂) aggregation, and to function as potential antioxidants and biometal chelators. In particular, compound 9 is a potential lead compound for AD treatment (for compound 9, IC₅₀ = 14.1 μM for the antioxidant activity using DPPH free radical method; 64.6% at 20 μM for self-induced Aβ aggregation). Moreover, it is capable of decreasing reactive oxygen species (ROS) induced by Cu-Aβ and shows good neuroprotective effects in human SH-SY5Y neuroblastoma cells. Taken together, these results suggest that 9 might be a promising lead compound for AD treatment.

Calyxin Y induces hydrogen peroxide-dependent autophagy and apoptosis via JNK activation in human non-small cell lung cancer NCI-H460 cells

Calyxin Y has been recently isolated from Alpinia katsumadai which has a folk use as an anti-tumor medicine. Calyxin Y induced caspase-dependent cell death in NCI-H460 cells, and concomitantly, provoked cytoprotective autophagy with the upregulation of critical Atg proteins. The cleavage of Atg proteins by caspases acted as a switch between autophagy and apoptosis induced by calyxin Y. Intracellular hydrogen peroxide (H2O2) production was triggered upon exposure to calyxin Y via the induction of autophagy and apoptosis. We provided evidence that activated JNK was upstream effectors controlling both autophagy and apoptosis in response to elevated H2O2. Therefore, our findings demonstrate that calyxin Y serves multiple roles as a promising chemotherapeutic agent that induces H2O2-dependent autophagy and apoptosis via JNK activation.

Multifunctional tacrine–flavonoid hybrids with cholinergic, β-amyloid-reducing, and metal chelating properties for the treatment of Alzheimer's disease

A new series of tacrine-flavonoid hybrids (13a-u) had been designed, synthesized, and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimers disease (AD). In vitro studies showed that most of the molecules exhibited a significant ability to inhibit ChE and self-induced amyloid-β (Aβ₁₋₄₂) aggregation. Kinetic and molecular modeling studies also indicated compounds were mixed-type inhibitors, binding simultaneously to active, peripheral and mid-gorge sites of AChE. Particularly, compound 13k was found to be highly potent and showed a balanced inhibitory profile against ChE and self-induced Aβ₁₋₄₂ aggregation. Moreover, it also showed excellent metal chelating property and low cell toxicity. These results suggested that 13k might be an excellent multifunctional agent for AD treatment.

Chukvelutins A-C, 16-norphragmalin limonoids with unprecedented skeletons from Chukrasia tabularis var. velutina.

Three new 16-norphragmalin limonoids, chukvelutins A-C (1-3), were isolated from the stem bark of Chukrasia tabularis var. velutina, which possess unprecedented skeletons, featured with a characteristic ketal moiety between the phragmalin skeleton and a biosynthetically extended isobutyryl group at C-15. Their structures were elucidated by extensive spectroscopic technologies.

Cytotoxic tirucallane C26 triterpenoids from the stem barks of Aphanamixis grandifolia.

Five tirucallane type C(26) triterpenoids, accompanied by two known compounds, 3α-hydroxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone and 3-oxo-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, were isolated from the stem barks of Aphanamixis grandifolia. Their structures were established mainly by means of a combination of 1D and 2D NMR spectroscopic and mass spectrometry techniques as 3α-hydroxyl-21α-methoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, 3α-hydroxy-21β-methoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, 3-oxo-21α-methoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, 3-oxo-21β-methoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, and 3-oxo-21α-ethoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone. All isolates were in vitro evaluated for their cytotoxic activities against five tumor cell lines (MCF-7, HeLa, HepG2, SGC-7901 and BGC-823).

Praeruptorin A enantiomers exert distinct relaxant effects on isolated rat aorta rings dependent on endothelium and nitric oxide synthesis.

Praeruptorin A is a coumarin compound naturally occurring in the roots of Peucedanum praeruptorum Dunn., a commonly used traditional Chinese medicine for the treatment of certain respiratory diseases and hypertension. Although previous studies indicated the relaxant effects of (+/-)-praeruptorin A on tracheal and arterial preparations, little is known about the functional characteristics of the enantiomers. In the present study, the two enantiomers were successfully isolated and identified by using a preparative Daicel Chiralpak AD-H column, and their relaxant effects on aorta rings were observed and compared. (+)-Praeruptorin A showed more potent relaxation than (-)-praeruptorin A against KCl- and phenylephrine-induced contraction of rat isolated aortic rings with intact endothelium. Removal of the endothelium remarkably reduced the relaxant effect of (+)-praeruptorin A but not that of (-)-praeruptorin A. Pretreatment of aortic rings with N(omega)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase) or methylene blue (MB, a soluble guanylyl cyclase inhibitor) resulted in similar changes of the relaxant effects of the two enantiomers to endothelium removal. Molecular docking studies also demonstrated that (+)-praeruptorin A was in more agreement to nitric oxide synthase pharmacophores than (-)-praeruptorin A. On the other hand, the two enantiomers of praeruptorin A could slightly attenuate the contraction of rat aortic rings induced by internal Ca(2+) release from sarcoplasmic reticulum (SR). These findings indicated that (+)-praeruptorin A and (-)-praeruptorin A exerted distinct relaxant effects on isolated rat aorta rings, which might be mainly attributed to nitric oxide synthesis catalyzed by endothelial nitric oxide synthase.

Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer's disease.

A series of tacrine-(β-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimers disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced β-amyloid (Aβ) aggregation, Cu(2+)-induced Aβ (1-42) aggregation, and to chelate metal ions. Especially, 11 l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of Aβ aggregation (65.8% at 20 μM) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11 l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11 l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11 l might be an excellent multifunctional agent for AD treatment.

Chuktabularins E-T, 16-Norphragmalin Limonoids from Chukrasia tabularis var. velutina.

Chuktabularins E-T (1-16), 16 new 16-norphragmalin limonoids, together with four known compounds, chuktabularins A-D, were isolated from the stem bark of Chukrasia tabularis var. velutina. These compounds possess a biosynthetically extended propionyl or acetyl group at C-15 and a characteristic ketal moiety between the limonoid skeleton and the acyl substituent at C-15. The structures of these compounds were established on the basis of detailed spectroscopic analysis, and that of 1 was confirmed by a single-crystal X-ray diffraction experiment, representing the first verification of the skeleton of 16-norphragmalin limonoids. Chuktabularins K-O (7-11) were found to be the first 19-acetoxylated 16-norphragmalin limonoids. Variable-temperature (1)H NMR experiments suggested that 7 exists as an equilibrium mixture of conformational isomers in solution. The absolute configuration of 5 was determined by the CD exciton chirality method on its 11,12-di-p-chlorobenzoate (5a), and those of 1-4 and 6-16 were proposed by correlating with 5 spectroscopically and biogenetically.