Alpinia galanga Willd., greater galangal, has been used for thousands of years as a spice as well as in traditional medicine. Its central nervous system (CNS) stimulant activity and neuroprotective effects have been proved both in animal models and human trials. However, the compounds responsible for these effects have not been identified yet. Therefore, the main constituents (p-OH-benzaldehyde (1), trans-p-coumaryl-alcohol (2), p-coumaryl-aldehyde (4), galanganol A (5), galanganol B (6), trans-p-acetoxycinnamyl alcohol (7), 1′S-1′-acetoxychavicol acetate (ACA, 9), and 1′S-1′-acetoxyeugenol acetate (AEA, 10)) were isolated to investigate their aqueous stability and passive diffusion across the gastro-intestinal tract (GIT) membrane and the blood–brain barrier (BBB) by the parallel artificial membrane permeability assay (PAMPA). Our positive results for compounds 1, 2, 4, 7, 9, and 10 suggest good permeability, thus potential contribution to the effects of greater galangal in the CNS. The results of the PAMPA-BBB were corroborated by in silico chemography-based ChemGPS-NP framework experiments. In addition, examination of the chemical space position of galangal compounds in relation to known psychostimulants revealed that all the molecules in proximity are NET/SERT inhibitors. As ACA and AEA did not show much proximity to either compound, the importance of further investigation of their degradation products becomes more pronounced.

Mitragynine is an “atypic opioid” analgesic with an alternative mechanism of action and a favorable side-effect profile. Our aim was to optimize the alkaloid extraction procedure from kratom leaves and to determine and isolate the most relevant compounds capable of penetrating the central nervous system. The PAMPA-BBB study revealed that mitragynine and its coalkaloids, speciociliatine, speciogynine, and paynantheine, possess excellent in vitro BBB permeability. An optimized sequence of CPC, flash chromatography, and preparative HPLC methods was used to isolate the four identified BBB+ alkaloids. To improve the bioavailability of the isolated alkaloids, their cyclodextrin (CD) complexation behavior was investigated via affinity capillary electrophoresis using almost 40 CD derivatives. The apparent alkaloid–CD complex stability constants were determined and compared, and the most relevant CDs phase-solubility studies were also performed. Both the neutral and negatively charged derivatives were able to form complexes with all four kratom alkaloids. It was found that cavity size, substituent type, and degree of substitution also influenced complex formation. The negatively charged Sugammadex, Subetadex, and the sufoalkylated-beta-CD analogs were able to form the most stable complexes, exceeding 1000 M⁻¹. These results serve as a good basis for further solubility and stability enhancement studies of kratom alkaloids.

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 P_e 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.

Four 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)—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.