Insight into Medicinal Chemistry Behind Traditional Chinese Medicines: p-Hydroxybenzyl Alcohol-Derived Dimers and Trimers from Gastrodia elata

Abstract

From an aqueous extract of "tian ma" (the steamed and dried rhizomes of Gastrodia elata), ten new compounds gastrodibenzins A-D (1-4) and gastrotribenzins A-F (5-10), along with known analogues (11-20), having structure features coupling between two and three p-hydroxybenzyl-derived units via carbon- and/or ether-bonds, were isolated and characterized by spectroscopic data analysis. Meanwhile, the new compounds 5a, 6a, 8a, 22, and 23, as well as the known derivatives 13a, 14a, 15, 17-21, 24, 25, and p-hydroxybenzyl aldehyde were isolated and identified from a refluxed aqueous solution of p-hydroxybenzyl alcohol. Methylation of 5a and 6a in methanol and ethylation of 6a, 8a, 13a, and 14a in ethanol produced 5 and 6 and 7, 8, 13, and 14, respectively. using ultra-performance liquid chromatography high-resolution electrospray ionization mass spectrometry (UPLC-HRESIMS) analysis of the refluxed solutions of p-hydroxybenzyl alcohol and the refluxed extracts of the fresh G. elata rhizome and "tian ma" extracts indicated consistent production and variation of the dimeric and trimeric derivatives of p-hydroxybenzyl alcohol upon extracting solvents and refluxing time. In various assays, the dimeric and trimeric derivatives showed more potent activities than p-hydroxybenzyl alcohol itself and gastrodin, which are the main known active constituents of "tian ma". These results revealed for the first time that the more effective dimers and trimers can be produced through condensation of the co-occurring p-hydroxybenzyl alcohol during processing and decocting of the G. elata rhizomes, demonstrating insights into medicinal chemistry behind application protocols of traditional Chinese medicines.

Keywords: Gastrodia elata; Gastrodibenzins; Gastrotribenzins; Medicinal chemistry behind Chinese medicines; Orchidaceae; p-Hydroxybenzyl alcohol dimer; p-Hydroxybenzyl alcohol trimer.

Fig. 1

Structures of compounds 1−25

Fig. 2

Main ¹H-¹H COSY (thick lines) and HMBC (arrows, from ¹H to ¹³C) correlations of compounds 1−11, 22, and 23

Fig. 3

Overlaid chromatograms of the extracted negative ion at m/z 349.145 [M − H]⁻: a, b compounds 5 and 6 in CH₃CN, respectively; c, d MeOH solutions of 5a and 6a were refluxed for 1 h, respectively; e MeOH solution of p-hydroxybenzyl alcohol was sonicated for 0.5 h then refluxed for 1.0 h

Fig. 4

Overlaid chromatograms of the extracted negative ion at m/z 363.161 [M − H]⁻: a−e compounds 7−11 in CH₃CN, respectively; (f, g) EtOH solutions of 6a and 8a were refluxed for 1.0 h, respectively; h EtOH solution of p-hydroxybenzyl alcohol was sonicated for 0.5 h then refluxed for 1.0 h

Fig. 5

Overlaid chromatograms of the extracted negative ion at m/z 257.119 [M–H]^–: a–c compounds 12–14 in CH₃CN, respectively; d, e EtOH solutions of 13a and 14a were refluxed for 1.0 h, respectively; f EtOH solution of p-hydroxybenzyl alcohol was sonicated for 0.5 h then refluxed for 1.0 h

Fig. 6

Overlaid chromatograms of the extracted negative ion at m/z 335.130 [M − H]⁻: (a−e) compounds 5a/6a, 8a, and 21−23 in CH₃CN, respectively; (f−h) extracts obtained by sonicating of fresh G. elata rhizomes with H₂O, MeOH, and EtOH for 0.5 h then refluxing for 2.0 h, respectively

Fig. 7

Overlaid chromatograms of the extracted negative ions at m/z 259.098 [M − H]⁻ for (a, b, d−f) and at 305.119 [M − H]⁻ for (c, g), respectively: (a−c) compounds 16, 24, and 18 in CH₃CN, respectively; (d−g) extracts obtained by sonicating of fresh G. elata rhizomes with H₂O, MeOH, and EtOH for 0.5 h then refluxing for 1.0 h or 2.0 h, respectively

Fig. 8

Overlaid chromatograms of the extracted negative ions at m/z 349.145 [M − H]⁻ for (a, b, f); and at 363.161 [M − H]⁻ for (c, d, g); and at 257.119 [M − H]⁻ for (e, h), respectively: (a−e) compounds 5, 6, 7, 9, and 14 in CH₃CN, respectively; (f−h) extracts obtained by sonicating of “tian ma” with MeOH and EtOH for 0.5 h then refluxing for 1.0 h or 2.0 h, respectively