RESUMO
Huperzia serrata, belonging to the Lycopodiaceae family, has been traditionally utilized for the management of treating rheumatic numbness, arthritic pain, dysmenorrhea, and contusions. This plant is a rich source of lycopodium alkaloids, some of which have demonstrated notable cholinesterase inhibitory activity. The objective of this study was to identify lycopodium alkaloids with cholinesterase inhibitory properties from H. serrata. The structures of these alkaloids were elucidated by HRESIMS, NMR (including a 1H-15N HMBC experiment), ECD methods and single-crystal X-ray diffraction. The inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were assessed using a modified Ellman's method. Consequently, sixteen lycopodium alkaloids (1-16), including ten previously undescribed ones named huperradines A-G and huperradines I-K (1-7 and 9-11), along with one previously undescribed naturally occurring compound, huperradine H (8), were isolated from H. serrata. Among these, compounds 7 and 1 exhibited potent and moderate AChE inhibition, with IC50 values of 0.876 ± 0.039 µM and 13.125 ± 0.521 µM, respectively. Our results suggest that huperradine G (7) may be a promising lead compound for the development of new AChE inhibitors for Alzheimer's disease.
Assuntos
Acetilcolinesterase , Alcaloides , Butirilcolinesterase , Inibidores da Colinesterase , Huperzia , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Alcaloides/química , Alcaloides/farmacologia , Alcaloides/isolamento & purificação , Huperzia/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Estrutura Molecular , Lycopodium/química , Relação Estrutura-Atividade , Relação Dose-Resposta a DrogaRESUMO
One new fawcettimine-type Lycopodium alkaloid, hupertimine F (1), together with five known (2-6) Lycopodium alkaloids were isolated from Huperzia goebelii. The structure of 1 was elucidated by 1D and 2D NMR spectra, HRESIMS, and X-ray diffraction. Structurally, 1 represents the fourth example of Lycopodium alkaloids characterized by a 5/5/5/5/6 pentacyclic ring system with a 1-aza-7-oxabicyclo[2.2.1]heptane moiety. These known compoundsâ 2, 3, 5, and 6 were isolated from H. goebelii for the first time. Compoundsâ 1-6 were evaluated for acetylcholinesterase, butyrylcholinesterase and monoamine oxidase B inhibitory activities inâ vitro.
Assuntos
Alcaloides , Huperzia , Lycopodium , Huperzia/química , Lycopodium/química , Butirilcolinesterase , Acetilcolinesterase/química , Estrutura Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Alcaloides/farmacologia , Alcaloides/químicaRESUMO
Two new dimeric Lycopodium alkaloids, casuattimines A and B (1 and 2), along with twelve previously undescribed Lycopodium alkaloids, casuattimines C-N (3-14), and eight known Lycopodium alkaloids, were isolated from Lycopodiastrum casuarinoides. Casuattimines A and B (1 and 2) are the first two ether-linked Lycopodium alkaloid dimers. Casuattimines C and D (3 and 4) are unique Lycopodium alkaloids characterized by a long fatty acid chain. Structural elucidation was achieved through HRESIMS, NMR, and electronic circular dichroism (ECD) calculations. In addition, the absolute configurations of compounds 7, 13, and 14 were determined by single crystal X-ray diffraction. Compounds 1, 2, and 4 demonstrated notable Cav3.1 channel inhibitory activities presenting IC50 values of 10.75 ± 1.02 µM, 9.33 ± 0.79 µM, and 7.14 ± 0.86 µM, respectively. The dynamics of compound 4 against the Cav3.1 channel and preliminary structure-activity relationships of these active Lycopodium alkaloids were also discussed.
Assuntos
Alcaloides , Lycopodiaceae , Lycopodium , Lycopodium/química , Estrutura Molecular , Inibidores da Colinesterase/farmacologia , Lycopodiaceae/química , Alcaloides/farmacologia , Alcaloides/químicaRESUMO
Hsp90, an ATP-dependent chaperone that is essential for a wide range of protein assembly and folding processes, has long been recognized as a potential target for cancer. Hsp90 has more recently been identified as having a significant pathogenic role in viral infection, neurodegenerative disease, and inflammation, therefore, the development of the agents to inhibit the chaperone could potentially treat such intractable diseases. Here, on the basis of primary structure-activity relationships and docking analysis, a series of novel vibsanin C analogues with an emphasis on the C18 position was first designed, synthesized and biologically evaluated. The most effective Hsp90 inhibitory activity among these analogues was demonstrated by 29 and 31, with IC50 values of 0.39 and 0.27 µM respectively. Direct interaction between Hsp90 and its inhibitors were further confirmed. Mechanism studies indicated that 29 promoted HL-60 cell apoptosis by mitochondrial-mediated apoptosis pathway. In addition, 29 suppressed tumor growth in the H22 tumor-bearing mice model and revealed low acute toxicity in mice (LD50 > 500 mg/kg), suggesting its potential for further investigations.
Assuntos
Anti-Inflamatórios não Esteroides , Antineoplásicos , Diterpenos , Desenho de Fármacos , Proteínas de Choque Térmico HSP90 , Animais , Camundongos , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Relação Estrutura-Atividade , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Diterpenos/química , Diterpenos/farmacologiaRESUMO
Three new clerodane-type diterpene glycosides, (5R,6S,8R,9S,10R)-6-O-[ß-D-glucopyranosyl-(1 â 4)-α-L-rhamnopyranosyl]cleroda-3,13(16),14-diene (1), (5R,6S,8R,9S,10R,13S)-6-O-[ß-D-glucopyranosyl-(1 â 4)-α-L-rhamnopyranosyl]-2-ox-oneocleroda-3,13-dien-15-ol (2), (5R,6S,8R,9S,10R)-6-O-[ß-D-glucopyranosyl-(1 â 4)-α-L-rhamnopyranosyl]-(13E)-2-oxoneocleroda-3,14-dien-13-ol (3), together with two known compounds 4 and 5 were isolated from Dicranopteris pedata. The structures of these compounds were elucidated by detailed spectroscopic analysis, and the absolute configuration of compound 2 was determined by ECD calculations. In addition, compound 1 exhibited weak inhibitory activities against SMMC-7721, MCF-7 and SW480.