•Many natural products exhibit anti-PD efficacy in vivo or vitro.•Many natural products possess good anti-oxidative and anti-inflammatory effects as well as suppressing protein misfolding.•The anti-PD properties of some natural products are closely related to PD related molecular signaling pathways.•Detailed investigations into the structure–activity relationships of natural products may guide the design of anti-PD drugs.Parkinson's disease (PD) is a common chronic degenerative disease of the central nervous system. Although the cause remains unknown, several pathological processes and central factors such as oxidative stress, mitochondrial injury, inflammatory reactions, abnormal deposition of α-synuclein, and cell apoptosis have been reported. Currently, anti-PD drugs are classified into two major groups: drugs that affect dopaminergic neurons and anti-cholinergic drugs. Unfortunately, the existing conventional strategies against PD are with numerous side effects, and cannot fundamentally improve the degenerative process of dopaminergic neurons. Therefore, novel therapeutic approaches which have a novel structure, high efficiency, and fewer side effects are needed. For many years, natural products have provided an efficient resource for the discovery of potential therapeutic agents. Among them, many natural products possess anti-PD properties as a result of not only their wellrecognized anti-oxidative and anti-inflammatory activities but also their inhibitory roles regarding protein misfolding and the regulatory effects of PD related pathways. Indeed, with the steady improvement in the technologies for the isolation and purification of natural products and the in-depth studies on the pathogenic mechanisms of PD, many monomer components of natural products that have anti-PD effects have been gradually discovered. In this article, we reviewed the research status of 37 natural products that have been discovered to have significant anti-PD effects as well as their mode of action. Overall, this review may guide the design of novel therapeutic drugs in PD.Download high-res image (244KB)Download full-size image

A sensitive and accurate LC method was developed and further validated for the determination of enantiomeric purity of GSK962040. Before separation, a pre-column derivatization procedure was performed. Baseline separation with a resolution higher than 1.9 was accomplished within 15 min using a Chiralpak AD-H (250 × 4.6 mm; particle size 5 μm) column, with n-hexane: 2-propanol (85:15 v/v) as mobile phase at a flow rate of 1 mL min−1. The eluted analytes were subsequently detected with a UV detector at 260 nm. The effects of mobile phase components and temperature on enantiomeric selectivity as well as resolution of enantiomers were thoroughly investigated. The calibration curves were plotted within the concentration range between 4 and 200 μg mL−1 (n = 8), and recoveries between 98.15 and 101.48% were obtained, with relative standard deviation (RSD) lower than 1.42%. The LOD and LOQ for the Boc-GSK962040 were 1.23 and 4.15 μg mL−1 and for its enantiomer were 1.38 and 4.76 μg mL−1, respectively. The developed method was also evaluated and validated by analyzing bulk samples with different enantiomeric ratios of GSK962040. It was demonstrated that the method was accurate, robust and sensitive, and also had practical utilities for real analysis.

A precise and sensitive LC method for the determination of repertaxin enantiomeric purity has been developed and validated. Baseline separation with a resolution higher than 2.0 was accomplished within 20 min using a Chiralpak AD-H column (250 × 4.6 mm; particle size 5 μm) and n-hexane:2-propanol (90:10 v/v) as mobile phase at a flow rate of 1 mL min−1. Eluted analytes were monitored by UV detection at 260 nm. The effects of mobile phase composition, temperature and flow rate on enantiomeric selectivity and on resolution of enantiomers were investigated. Calibration curves were plotted within the concentration range between 0.002 and 1.0 mg mL−1 (n = 3), and relative standard deviation (RSD) of the inter-batch assay and intra-batch assay was less than 1.27 and 1.16 %. LOD and LOQ for repertaxin were 0.65 and 2.19 μg mL−1; those for its enantiomer were 0.70 and 2.34 μg mL−1, respectively. The method was evaluated and validated by analysis of bulk samples of repertaxin of different enantiomeric purity. It was demonstrated that the method was accurate, robust, and sensitive, and enabled practical analysis of real samples.

A precise and sensitive LC method was developed and further validated for the determination of enantiomeric purity of (S)-N-[2-(3-{trans-4-hydroxy-4-[5-(pyrimidin-2-yl)pyridin-2-yl] cyclohexylamino} pyrrolidin-1-yl)-2-oxoethyl]-3-(trifluoromethyl) benzamide (PF-04136309). Baseline separation with a resolution higher than 1.8 was accomplished within 40 min using a CHIRALPAK AD (250 × 4.6 mm; particle size 5 μm) column, with n-hexane:2-propanol (70:30 v/v) as mobile phase at a flow rate of 1 mL min−1. The eluted analytes were subsequently detected with a UV detector at 260 nm. The effects of mobile phase components and temperature on enantiomeric selectivity as well as the resolution of enantiomers were thoroughly investigated. The calibration curves were plotted within a concentration range between 0.01 and 1 mg mL−1 (n = 9), and recoveries between 98.17 and 101.28 % were obtained, with relative standard deviation (RSD) lower than 1.44 %. The LOD and LOQ for PF-04136309 were 3.59 and 11.54 μg mL−1 and for its enantiomer were 3.39 and 11.28 μg mL−1, respectively. The developed method was demonstrated to be accurate, robust and sensitive for the determination of enantiomeric purity of PF-04136309, especially for the analysis of bulk samples.

A precise and sensitive LC method for determination of enantiomeric purity of trelagliptin has been developed and validated. Pre-column derivatization was performed before separation. Baseline separation with a resolution factor >2.5 was accomplished within 10 min by use of a Chiralpak AD column (250 × 4.6 mm; particle size 5 µm) and n-hexane–2-propanol (90:10 v/v) as mobile phase at a flow rate of 1 mL min−1. Eluted analytes were monitored by UV detection at 260 nm. The effects of mobile phase composition and temperature on enantiomeric selectivity and on resolution of enantiomers were thoroughly investigated. Calibration curves were plotted within the concentration range 0.005–2 mg mL−1 (n = 12), and recoveries between 98.23 and 101.34 % were obtained, with relative standard deviation (RSD) <1.39 %. LOD and LOQ for the trelagliptin derivative were 1.51 and 5.03 µg mL−1; those for its enantiomer were 1.49 and 4.94 µg mL−1, respectively. The method was evaluated and validated by analysis of bulk samples of trelagliptin of different enantiomeric purity. It was demonstrated that the method was accurate, robust, and sensitive, and enabled practical analysis of real samples.

An efficient synthesis of novel endo′-selective spiro[pyrrolidin-2,3′-oxindoles] has been achieved via a three component regioselective 1,3-dipolar cycloaddition reaction. The azomethine ylides generated in situ from 3-amino oxindoles and aldehydes reacted with the nitroalkenes to furnish novel pyrrolidine–spirooxindole derivatives bearing one spiro quaternary center and multiple chiral centers in moderate to high yields (up to 99%) with high diastereoselectivities (up to 99:1). The structure and relative stereochemistry of cycloadducts were confirmed by NMR spectra and single crystal X-ray diffraction. The possible mechanism was proposed and the cycloaddition proceeded via endo′-transition state.

A rapid and sensitive LC method was developed and validated for the determination of diastereomeric purity of tenofovir alafenamide (GS-7340). Baseline separation with resolution >2.8 was achieved within 17 min on a CHIRALPAK AD-3 (250 × 4.6 mm; particle size 3 μm) column using n-hexane:2-propanol (60:40 v/v) as the mobile phase at a flow rate of 1 mL min−1. The analytes were detected by UV absorbance at 260 nm. The effects of ethanol, 2-propanol, and temperature on diastereomeric selectivity and resolution of diastereomerism were evaluated. The method was extensively validated and proved to be robust. The recoveries were between 98.17 and 102.84 % with <1.93 % relative standard deviation. The limit of detection and limit of quantitation for GS-7339 were 0.77 and 2.56 μg mL−1 and for GS-7340 were 0.61 and 2.04 μg mL−1, respectively. This method was extensively proved to be accurate, stable, rapid, and sensitive for the determination of diastereomeric purity of tenofovir alafenamide (GS-7340) in bulk samples.