Quassinoids from Twigs of Harrisonia perforata (Blanco) Merr and Their Anti-Parkinson's Disease Effect

Abstract

Six new C-20 and one new C-19 quassinoids, named perforalactones F-L (1-7), were isolated from twigs of Harrisonia perforata. Spectroscopic and X-ray crystallographic experiments were conducted to identify their structures. Through oxidative degradation of perforalactone B to perforaqussin A, the biogenetic process from C-25 quassinoid to C-20 via Baeyer-Villiger oxidation was proposed. Furthermore, the study evaluated the anti-Parkinson's disease potential of these C-20 quassinoids for the first time on 6-OHDA-induced PC12 cells and a Drosophila Parkinson's disease model of PINK1^B9. Perforalactones G and I (2 and 4) showed a 10-15% increase in cell viability of the model cells at 50 μM, while compounds 2 and 4 (100 μM) significantly improved the climbing ability of PINK1^B9 flies and increased the dopamine level in the brains and ATP content in the thoraces of the flies.

Keywords: Harrisonia perforata; PC12 cells; PINK1B9 flies; neuroprotection; quassinoid; simarubaceae.

Figure 1

Chemical structures of ruthenine A, harpertrioate A, perforalactone B, perforalactones D and E.

Figure 2

Structures of compounds 1–8.

Figure 3

¹H-¹H COSY and key HMBC correlations of compounds 1–7.

Figure 4

Key ROESY correlations of compounds 1–7.

Figure 5

X-ray crystallographic structure of 7.

Scheme 1

(A) Updated hypothesis for the biosynthetic pathway of C₂₀ quassinoids, and proposed step in this work in blue. (B) Chemical transformation (in plain) and proposed mechanism (in dashed) of quassinoid from C₂₅ quassinoid to C₂₀ one.

Figure 6

Neuroprotective effects of isolated compounds against 6-OHDA-induced injury in PC12 cells. (A) Neuroprotective effect of the isolated compounds at 50 μM. (B) Neuroprotective effect of compounds 1, 2, 4, and 5 at various concentrations (25, 50, and 100 μM). (C) Cytotoxic effect of compounds 1, 2, 4, and 5 (25, 50, and 100 μM) on the PC12 cell. Data were expressed as the means ± SD of three independent experiments. * p < 0.05, ** p < 0.01, and *** p < 0.001 compared with model cells in (A,B) and compared with control cells in (C). Rasagiline (Ras) was used as a positive control.

Figure 7

Neuroprotective effect of the isolated compounds (1, 2, 4, and 5 at the concentration of 0.1% (v/v)) on PINK1^B9 flies. (A) Climbing abilities of WT flies, PINK1^B9, and PINK1^B9 treated with isolated compounds at 6 days. (B) ATP levels of WT flies, PINK1^B9, and PINK1^B9 treated with isolated compounds at 6 days. (C) Dopamine levels of WT flies, PINK1^B9, and PINK1^B9 treated with isolated compounds at 18 days. Data from three times independent experiments were expressed as means ± SD, and * p < 0.05, and ** p < 0.01 compared with PINK1^B9 flies.