Membrane Permeability and Aqueous Stability Study of Linear and Cyclic Diarylheptanoids from Corylus maxima

Abstract

Seven diarylheptanoids were isolated from Corylus maxima by flash chromatography and semipreparative high-performance liquid chromatography (HPLC) and identified by Orbitrap® mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy as linear diarylheptanoids: hirsutanonol-5-O-β-D-glucopyranoside (1), platyphyllonol-5-O-β-D-xylopyranoside (4), platyphyllenone (5); and cyclic derivatives: alnusonol-11-O-β-D-glucopyranoside (6), alnusone (7), giffonin F (8), carpinontriol B (9). Cyclic diarylheptanoids are reported in C. maxima for the first time. The aqueous stability of the isolated compounds and other characteristic constituents of C. maxima, oregonin (2), hirsutenone (3), quercitrin (10) and myricitrin (11) was evaluated at pH 1.2, 6.8 and 7.4. The passive diffusion of the constituents across biological membranes was investigated by parallel artificial membrane permeability assay for the gastrointestinal tract (PAMPA-GI) and the blood–brain barrier (PAMPA-BBB) methods. The cyclic diarylheptanoid aglycones and quercitrin were stable at all investigated pH values, while a pH-dependent degradation of the other compounds was observed. A validated ultrahigh-performance liquid chromatography-diode-array detection (UHPLC-DAD) method was utilized for the determination of compound concentrations. The structures of the degradation products were characterized by UHPLC-Orbitrap® MS. Platyphyllenone and alnusone possessed log Pe values greater than −5.0 and −6.0 in the PAMPA-GI and PAMPA-BBB studies, respectively, indicating their ability to cross the membranes via passive diffusion. However, only alnusone can be considered to have both good aqueous stability and satisfactory membrane penetration ability.

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

“…Compound 4 was stable only at pH 7.4 after 81 h, while in agreement with our recent results [12], compound 2 remained intact for the whole study at all pH values. Therefore, rate constants and half-lives in these cases have not been determined.…”

“…Degradation of hirsutenone is further facilitated by the elevation of the temperature: the half-life of hirsutenone in aqueous solution is reduced from 5.78 days at 25 °C to 1.59 days at 50 °C [11]. Although there are several stability testing studies regarding linear diarylheptanoids, the chemical stability of the cyclic derivatives is underexplored [12]. Cyclic-type diarylheptanoids are characteristic of species belonging to the genera Carpinus [13] or Corylus [14,15] in the Betulaceae family.…”

“…In our previous work, we identified the characteristic meta,meta-cyclophane-type cyclic diarylheptanoids carpinontriols A (1) and B (2), giffonin X (3) and 3,12,17-trihydroxytricyclo [12.3.1.1 2,6 ]nonadeca-1(18),2(19),3,5,14,16-hexaene-8,11-dione (4) (Figure 2) in European hornbeam (Carpinus betulus L., Betulaceae) for the first time [16]. Although there are several stability testing studies regarding linear diarylheptanoids, the chemical stability of the cyclic derivatives is underexplored [12]. Cyclic-type diarylheptanoids are characteristic of species belonging to the genera Carpinus [13] or Corylus [14,15] in the Betulaceae family.…”

BrainPepPass: A Framework Based on Supervised Dimensionality Reduction for Predicting Blood-Brain Barrier-Penetrating Peptides

“…This technique utilizes a porcine polar brain lipid artificial membrane between the donor and acceptor compartments to predict the blood-brain barrier permeation of molecular compounds, including peptides. This technique, in its different variants, has been used to classify the permeability of various compounds in the brain, including 3-hydroxy-2-pyridinealdoxime, furosemide, ranitidine, donepezil, tacrine, platyphyllenone, alnusone, gingerol, and shogaol derivatives …”

“…This technique utilizes a porcine polar brain lipid artificial membrane between the donor and acceptor compartments to predict the blood-brain barrier permeation of molecular compounds, including peptides. This technique, in its different variants, has been used to classify the permeability of various compounds in the brain, including 3-hydroxy-2-pyridinealdoxime, 46 furosemide, ranitidine, donepezil, tacrine, 47 platyphyllenone, alnusone, 48 gingerol, and shogaol derivatives. 49 The apparent permeability coefficient (P app ) is a similar indicator used to evaluate the in vitro ability of a molecule to traverse a cell barrier, such as the blood-brain barrier, and is expressed in units of cm/s.…”