A Grand Challenge. 3. Unbiased Phenotypic Function of Metabolites from Australia Plants Gloriosa superba and Alangium villosum against Parkinson’s Disease

Abstract

As part of a continuing research program aiming to identify chemical probes to interrogate Parkinson's disease (PD), we have investigated the Australian plants Gloriosa superba and Alangium villosum. The chemical investigations of G. superba resulted in the isolation of four new alkaloids, β-lumicolchicosides A−C (1−3) and γ-lumicolchicoside A (4), together with four lumicolchicine derivatives (5−8) and six colchicine analogues (9− 14) as known structures. The chemical investigations of A. villosum resulted in the isolation of four new benzoquinolizidine N-oxides, tubulosine N β 5 -oxide (15), isotubulosine N α 5 -oxide (16), 9demethyltubulosine N β 5 -oxide (17), and 9-demethylisotubulosine N α 5 -oxide (18), together with five known benzoquinolizidine alkaloids (19−23). The chemical structures of the new compounds (1−4 and 15−18) were characterized unambiguously by extensive analysis of their NMR and MS data. Unbiased multidimensional profiling was used to investigate the phenotypic profiles of all of the metabolites. The results show that the lead probes have different effects on cellular organelles that are implicated in PD in patient-derived cells.

Antiproliferative Potential of Gloriosine: A Lead for Anticancer Drug Development

“…All of the isolated compounds were characterized by matching with their reported 1 H and 13 C NMR values ( Supporting Information ). Isolated compounds were identified as stigmasterol ( 1 ), 15 β-sitosterol ( 2 ), 15 trioxsalen ( 3 ), 16 caffeic acid ( 4 ), 17 6-methoxysalicylic acid ( 5 ), 18 β-lumicolchicine ( 6 ), 19 N -deacetyl- N -formyl-β-lumicolchicine ( 7 ), 20 2-demethyl-β-lumicolchicine ( 8 ), 19 γ-lumicolchicine ( 9 ), 19 colchicine ( 10 ), 21 gloriosine ( 11 ), 22 3-demethylcolchicine ( 12 ), 21 3-demethyl- N -deacetyl- N -formyl colchicine ( 13 ), 22 and colchicoside ( 14 ) 23 ( Figure 2 ).…”

Meeting the Challenge 2: Identification of Potential Chemical Probes for Parkinson’s Disease from Ligusticum chuanxiong Hort Using Cytological Profiling

“…Combining TCM and phenotypic screening against hONS cells has great potential for finding small molecules as chemical tools for PD research. Indeed, many successful investigations with a similar experimental direction have been described. − In this article, we demonstrate another case study of utilizing this approach. This present article outlines the combination of chemistry and biology in which the chemical constituents of the TCM Ligusticum chuanxiong Hort were extensively investigated, followed by an in-depth phenotypic analysis of the obtained secondary metabolites against the olfactory epithelium-derived cells from a PD patient to identify hit compounds.…”

“…The cytological profiling assay, which includes the hONS cell culture, compound preparation, cell staining, cell imaging, and image analysis, conducted in this study followed the same protocols previously reported. − Clustering was performed on Cluster 3.0 (Stanford University) using centroid linkage and the uncentered Pearson correlation coefficient metric; the clustered data were subsequently visualized and processed in Java TreeView (Stanford University), from which heatmaps were also generated. Cosine similarity scores were calculated using the formula reported by Han et al…”