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. 2023 Aug 30;24(17):13489.
doi: 10.3390/ijms241713489.

Evaluation of the Chemical Stability, Membrane Permeability and Antiproliferative Activity of Cyclic Diarylheptanoids from European Hornbeam (Carpinus betulus L.)

Csenge Anna Felegyi-Tóth  1 , Tímea Heilmann  1 , Eszter Buda  1 , Bence Stipsicz  2   3 , Alexandra Simon  1 , Imre Boldizsár  1   4 , Szilvia Bősze  3   5 , Eszter Riethmüller  1 , Ágnes Alberti  1
Affiliations

Evaluation of the Chemical Stability, Membrane Permeability and Antiproliferative Activity of Cyclic Diarylheptanoids from European Hornbeam (Carpinus betulus L.)

Csenge Anna Felegyi-Tóth et al. Int J Mol Sci. .

Abstract

Four cyclic diarylheptanoids-carpinontriols A (1) and B (2), giffonin X (3) and 3,12,17-trihydroxytricyclo [12.3.1.12,6]nonadeca-1(18),2(19),3,5,14,16-hexaene-8,11-dione (4)-were isolated from Carpinus betulus (Betulaceae). Chemical stability of the isolated diarylheptanoids was evaluated as a function of storage temperature (-15, 5, 22 °C) and time (12 and 23 weeks). The effect of the solvent and the pH (1.2, 6.8, 7.4) on the stability of these diarylheptanoids was also investigated. Compounds 2 and 4 showed good stability both in aqueous and methanolic solutions at all investigated temperatures. Only 2 was stable at all three studied biorelevant pH values. Degradation products of 1 and 3 were formed by the elimination of a water molecule from the parent compounds, as confirmed by ultrahigh-performance liquid chromatography-high-resolution tandem mass spectrometry (UHPLC-HR-MS). The permeability of the compounds across biological membranes was evaluated by the parallel artificial membrane permeability assay (PAMPA). Compound 3 possesses a logPe value of -5.92 ± 0.04 in the blood-brain barrier-specific PAMPA-BBB study, indicating that it may be able to cross the blood-brain barrier via passive diffusion. The in vitro antiproliferative activity of the compounds was investigated against five human cancer cell lines, confirming that 1 inhibits cell proliferation in A2058 human metastatic melanoma cells.

Keywords: PAMPA; antiproliferative activity; chemical stability; degradation products; diarylheptanoid; mass spectrometry.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Scheme 1
Scheme 1
The possible degradation pathways of compound 1 and the proposed mass spectrometric fragmentation of the degradation product 1c (A); the possible degradation pathways of compound 3 and the proposed mass spectrometric fragmentation of the degradation product 3a (B). Degradation product numbers refer to Table 5.
Figure 1
Figure 1
The structures of linear, meta,meta-cyclophane-type and meta,para-cyclophane-type diarylheptanoids (A); structures of curcumin and hirsutenone (B).
Figure 2
Figure 2
Structures of the investigated cyclic diarylheptanoids: (1) carpinontriol A, (2) carpinontriol B, (3) giffonin X, (4) 3,12,17-trihydroxytricyclo [12.3.1.12,6]nonadeca-1(18),2(19),3,5,14,16-hexaene-8,11-dione.
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