RESUMO
Five new fawcettimine-type Lycopodium alkaloids, hupertimines A-E (1-5), were discovered from the whole plant of Huperzia serrata, along with two known alkaloids, 8α-hydroxyphlegmariurine B (6) and 8ß-hydroxyphlegmariurine B (7). The structures of 1-7 were identified through HR-MS, IR, 1 H, 13 C, and 2D NMR, and single-crystal X-ray diffraction analysis. Structurally, compound 1 was the fourth example of Lycopodium alkaloid with an ether linkage between C-5 and C-13 and 2 was the third example of Lycopodium alkaloid with a 5/5/5/5/6 pentacyclic ring system and featuring a 1-aza-7-oxabicyclo[2.2.1]heptane unit. Compounds 1-7 were tested for their BACE1 inhibitory activity. In addition, the correct 1 H- and 13 C-NMR data for 7 were reported in current study.
Assuntos
Alcaloides , Huperzia , Lycopodium , Alcaloides/química , Alcaloides/farmacologia , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Huperzia/química , Lycopodium/química , Estrutura MolecularRESUMO
Four new fawcettimine-related alkaloids (1-4), together with 17 known ones, were isolated from club moss Phlegmariurus squarrosus. Notably, compound 1 was the derivative of lycoflexine with an unprecedented additional methyl group at C-17. Their structures were determined by extensive spectroscopic analysis, including 1D and 2D NMR, and HR-MS, as well as by comparison with the literature data. All new compounds were tested for their ß-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) and acetylcholinesterase (AChE) inhibitory activities.
Assuntos
Alcaloides/química , Inibidores da Colinesterase/isolamento & purificação , Lycopodiaceae/química , Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Ácido Aspártico Endopeptidases/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Estrutura Molecular , Ressonância Magnética Nuclear BiomolecularRESUMO
The fruits of Alpinia oxyphylla (Alpiniae Oxyphyllae Fructus, AOF) are one of the "Four Famous South Medicines" in China. In this study, beta-site amyloid protein precursor cleaving enzyme 1 (BACE1) was applied to explore the active components in AOF responsible for type 2 diabetes mellitus (T2DM)-related cognitive disorder. As a result, 24 compounds including three unreported ones (1, 3, 4) were isolated from AOF. Compound 1 is an unusual carboncarbon linked diarylheptanoid dimer, and compound 4 is the first case of 3,4-seco-eudesmane sesquiterpenoid with a 5/6-bicyclic skeleton. Four diarylheptanoids (3, 5-7), one flavonoid (9) and two sesquiterpenoids (14 and 20) showed BACE1 inhibitory activity, of which the most active 6 was revealed to be a non-competitive and anti-competitive mixed inhibitor. Docking simulation suggested that OH-4' of 6 played important roles in maintaining activity by forming hydrogen bonds with Ser36 and Ile126 residues. Compounds 3, 5, 9 and 20 displayed neuroprotective effects against amyloid ß (Aß)-induced damage in BV2 cells. Mechanism study revealed that compounds 5 and 20 downregulated the expression of BACE1 and upregulated the expression of Lamp2 to exert effects. Thus, the characteristic diarylheptanoids and sesquiterpenoids in AOF had the efficacy to alleviate T2DM-related cognitive disorder by inhibiting BACE1 activity and reversing Aß-induced neuronal damage.
Assuntos
Alpinia , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Diabetes Mellitus Tipo 2 , Frutas , Sesquiterpenos , Alpinia/química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Frutas/química , Estrutura Molecular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Sesquiterpenos/farmacologia , Sesquiterpenos/isolamento & purificação , Simulação de Acoplamento Molecular , Diarileptanoides/farmacologia , Diarileptanoides/isolamento & purificação , Diarileptanoides/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Humanos , Animais , China , Flavonoides/farmacologia , Flavonoides/isolamento & purificação , Flavonoides/química , Transtornos Cognitivos/tratamento farmacológico , Camundongos , Extratos VegetaisRESUMO
Three new lycodine-type Lycopodium alkaloids, namely 1-methyllycodine (1), 8α-hydroxy-15,16-dehydro-des-N-methyl-α-obscurine (2), N-methyl-16-hydroxyhuperzine B (3), and one new natural lycodine-type Lycopodium alkaloid, N-methylhuperzine A (4), along with 11 known analogues (5-15), were isolated from the whole plants of club moss Huperzia serrata. The structures of 1-4 were elucidated on the basis of NMR spectroscopic and mass spectrometry data. Among them, compound 1 was the first lycodine-type alkaloid possessing a methyl group at C-1. In addition, the structure of 5 was confirmed by the single-crystal X-ray crystallography data and its 13C NMR was reported for the first time in current study. Compounds 1-5 were tested their BACE1 inhibitory activity.
RESUMO
Inhibition of ß-secretase (BACE1) is currently regarded as the leading treatment strategy for Alzheimer's disease. In the present study, we aimed to screen the in vitro inhibitory activity of 80 types of aroma compounds (monoterpenes, sesquiterpenes, and C13 norisoprenoids), including plant-based types, at a 200-µM concentration against a recombinant human BACE1. The results showed that the most potent inhibitor of BACE1 was geranyl acetone followed by (+)-camphor, (-)-fenchone, (+)-fenchone, and (-)-camphor with the half-maximal inhibitory concentration (IC50) values of 51.9 ± 3.9, 95.9 ± 11.0, 106.3 ± 14.9, 117.0 ± 18.6, and 134.1 ± 16.4 µM, respectively. Furthermore, the mechanism of inhibition of BACE1 by geranyl acetone was analyzed using Dixon kinetics plus Cornish-Bowden plots, which revealed mixed-type mode. Therefore aroma compounds may be used as potential lead molecules for designing anti-BACE1 agents.