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.
Traditional Chinese medicine (TCM) has been around for
thousands
of years and is increasingly gaining popularity in the Western world
to treat various complex disorders including the incurable neurodegenerative
condition, Parkinson’s Disease (PD). One of the many directions
in recent studies of PD is utilizing the phenotypic assay, or cytological
profiling, to evaluate the phenotypic changes of PD-implicated cellular
components in patient-derived olfactory neuroepithelial (hONS) cells,
upon treating the cells with extracts or pure compounds. To obtain
small molecules for studies utilizing PD phenotyping assays, Ligusticum chuanxiong Hort was selected for analysis
as it is a popular Chinese herbal medicine used for treating PD-like
symptoms. Fifty-three secondary metabolites, including six new compounds,
were isolated from the ethanolic extract of L. chuanxiong; their structures were elucidated based on several spectroscopic
techniques such as NMR, MS, Fourier transform infrared (FTIR), UV,
and theoretical density functional theory (DFT) calculations. Cytological
profiling of the afforded natural products against PD hONS cells revealed
34 compounds strongly perturbated the staining of several cellular
organelles. In fact, greaterthan 1.5-fold change was observed compared
to the control (dimethyl sulfoxide; DMSO), with early endosome, lysosome,
and autophagosome (LC3b) being particularly affected. Given these
biological compartments are closely related to PD pathogenesis, the
results helped rationalize the traditional medicinal use of L. chuanxiong in PD treatment. Further, the hit
compounds can serve as chemical probes to map the molecular pathways
underlying PD, potentially leading to new therapeutic targets for
PD.
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