RESUMO
Natural products and their analogues are significant sources of therapeutic lead compounds. However, synthetic strategies for generating large collections of these molecules remain a significant challenge. The most difficult step in their synthesis is the design of a common intermediate that can be easily transformed into natural products belonging to different families. This study demonstrates the evolution of synthetic tactics designed to assemble the functionalized piperidines present in indole alkaloids from a common intermediate. More importantly, we also report a previously unknown Ir- and Er-catalyzed dehydrogenative spirocyclization reaction that enables direct access to spirocyclic oxindole alkaloids. As a practical application, the asymmetric total syntheses of 29 natural alkaloids belonging to different families were accomplished by following a uniform synthetic route. The proposed methodology extends the capability of the iridium-catalyzed dehydrogenative coupling reaction to the realm of indole-alkaloid synthesis and provides new opportunities for the efficient preparation of natural product-like molecules.
Assuntos
Alcaloides , Produtos Biológicos , Humanos , Estereoisomerismo , Alcaloides Indólicos , OxindóisRESUMO
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
Lycopodiales, an order comprising 388 distinct species, is the source of Lycopodium alkaloids (LAs), a group of naturally occurring alkaloids that share a common biosynthesis and structural attributes. These remarkable organisms are considered vestiges of ancient ferns, with fossil evidence dating their existence back to an impressive 300â million years. LAs usually are tricyclic or tetracyclic compounds with C16N or C16N2 skeleton. But then there are also have a few C11N, C15N, C15N2, C22N2, and C27N3 skeleton. LAs have attracted much scientific attention because of their important biological activities related to acetylcholinesterase and unique structural characteristics. From 1881 to December 2023, there are 593 LAs from 49 species of Lycopodiales have been reported. Because the total amount of LAs is nearly five times that of 1994, the classification and group allocation of some newly isolated LAs is often challenging and not unambiguous by Ayer's simple classification. This review makes a more systematic and detailed classification for it and provides extensive coverage of naturally occurring LAs discovered from 1881 to December 2023. Until now, there is no comprehensively summary of biological activity of the LAs. This review is the first time covered the biological activity of the all LAs.
RESUMO
Voltage-gated calcium channels (VGCCs), particularly T-type calcium channels (TTCCs), are crucial for various physiological processes and have been implicated in pain, epilepsy, and cancer. Despite the clinical trials of TTCC blockers like Z944 and MK8998, none are currently available on the market. This study investigates the efficacy of Lycopodium alkaloids, particularly as natural product-based TTCC blockers. We synthesized eighteen derivatives from α-obscurine, a lycodine-type alkaloid, and identified five derivatives with significant Cav3.1 blockade activity. The most potent derivative, compound 7, exhibited an IC50 value of 0.19±0.03â µM and was further analyzed through molecular docking, revealing key interactions with Cav3.1. These findings provide a foundation for the structural optimization of Cav3.1 calcium channel blockers and present compound 7 as a promising lead compound for drug development and a tool for chemical biology research.
Assuntos
Alcaloides , Bloqueadores dos Canais de Cálcio , Humanos , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/química , Simulação de Acoplamento Molecular , Alcaloides/farmacologia , Alcaloides/química , Dor , CálcioRESUMO
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
Taxodin A (1), a unique C30 terpenoid featuring an unprecedented skeleton composed of an abietane-type diterpene and a menthane-type monoterpene, was obtained from the leaves and branches of Taxodium mucronatum. The structure and absolute configuration of compound 1 was unequivocally established by the combination of extensive spectroscopic analyses and X-ray single-crystal diffraction analysis. Compound 1 exhibited potent cytotoxic activities against A549, SMMC-7721, MDA-MB-231, and SW480â cell lines with IC50 values of 15.35±0.73, 8.49±0.35, 17.53±0.79, 18.93±0.60â µM, respectively.
Assuntos
Antineoplásicos Fitogênicos , Ensaios de Seleção de Medicamentos Antitumorais , Taxodium , Humanos , Taxodium/química , Linhagem Celular Tumoral , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Terpenos/química , Terpenos/farmacologia , Terpenos/isolamento & purificação , Conformação Molecular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Folhas de Planta/química , Relação Estrutura-Atividade , Estrutura Molecular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Modelos MolecularesRESUMO
A novel Lycopodium alkaloid, lycocasine A (1), and seven known Lycopodium alkaloids (2-8), were isolated from Lycopodiastrum casuarinoides. Their structures were determined through NMR, HRESIMS, and X-ray diffraction analysis. Compound 1 features an unprecedented 5/6/6 tricyclic skeleton, highlighted by a 5-aza-tricyclic[6,3,1,02,6]dodecane motif. In bioactivity assays, compound 1 demonstrated weak inhibitory activity against acid-sensing ion channel 1a.
Assuntos
Alcaloides , Lycopodiaceae , Lycopodium , Canais Iônicos Sensíveis a Ácido , Alcaloides/farmacologia , AzacitidinaRESUMO
Cyclovirobuxine-D (CVB-D) is a Buxus alkaloid and a major active constituent in the Chinese medicinal herb Buxus microphylls. Traditionally, the natural alkaloid cyclovirobuxine-D has a long history of use as a traditional Chinese medicine for cardiovascular diseases as well as to treat a wide variety of medical conditions. As we found that CVB-D inhibited T-type calcium channels, we designed and synthesized a variety of fragments and analogues and evaluated them for the first time as new Cav3.2 inhibitors. Compounds 2-7 exhibited potency against Cav 3.2 channels, and two of them were more active than their parent molecules. As a result of the in vivo experiments, both compounds 3 and 4 showed significantly reduced writhes in the acetic acid-induced writhing test. Studies of molecular modeling have identified possible mechanism(s) of Cav3.2 binding. Moreover, the relationship between structure and activity was studied in a preliminary manner. Our results indicated that compounds 3 and 4 could play an important role in the discovery and development of novel analgesics.
Assuntos
Alcaloides , Antineoplásicos , Buxus , Canais de Cálcio Tipo T , Alcaloides/farmacologia , Analgésicos/farmacologia , Buxus/químicaRESUMO
Two pairs of unprecedented enantiomeric phthalide dimers, spiroligustolides A (1a/1b) and B (2a/2b), featuring a unique spiroorthoster linkage between two monomeric units to form a 5/6/5/6/6-fused ring system, were isolated from the roots of Ligusticum chuanxiong. The structures and relative configurations of 1 and 2 were determined by HR-ESI-MS, IR, and NMR spectroscopic data, coupled with single-crystal X-ray diffraction analysis, and the absolute configurations of 1a, 1b, 2a, and 2b were established by comparing the experimental and calculated electronic circular dichroism (ECD) data. Plausible biosynthetic pathway for 1 and 2 was proposed. Moreover, compounds 1, 1b, and 2b showed remarkable inhibitory activities on Cav3.1 calcium channel with IC50 values of 8.34, 7.08, and 8.60 µM, respectively.
Assuntos
Benzofuranos , Ligusticum , Benzofuranos/química , Benzofuranos/farmacologia , Canais de Cálcio , Ligusticum/química , Estrutura Molecular , EstereoisomerismoRESUMO
Vibsane-type diterpenoids isolated from the genus Viburnum, are rare 6-11 membered ring polysubstituted macrocyclic diterpenoids. Since the first report of vibsane-type diterpenoids from V. odoratissimum in 1980, they have attracted the attention of scientists due to their complex structures, excellent biological activities, and great synthetic challenges. Recently, there are some notable research achievements on the discovery, synthesis, structural modification, and pharmacological mechanism of vibsane-type diterpenoids. Therefore, we will focus on these aspects to review important achievements of vibsane diterpenoids between 1980-2021.
Assuntos
Diterpenos , Viburnum , Diterpenos/química , Diterpenos/farmacologia , Estrutura Molecular , Viburnum/químicaRESUMO
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
Two new seco-prezizaane-type sesquiterpenes, 2ß-hydroxy-6-deoxyneoanisatin (1) and 3,4-anhydro-2-oxo-1α-hydroxy-6-deoxyneoanisatin (2), and two new prenylated C6 -C3 compounds, illilanceofunones A (3) and B (4), were obtained from the fruits of Illicium lanceolatum, along with four known prenylated C6 -C3 compounds (5-8). Their structures were proposed through HR-ESI-MS, 1 H, 13 C, and 2D NMR data interpretation. Moreover, the absolute configuration of 1 and 2 were further assigned by single-crystal X-ray diffraction analysis and electronic circular dichroism (ECD) calculations, respectively. Illihenryipyranol A (6) exhibited neuroprotective activity against MPP+ -induced PC12â cell damage in a dose-dependent manner.
Assuntos
Illicium/química , Fármacos Neuroprotetores/química , Sesquiterpenos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Frutas/química , Frutas/metabolismo , Illicium/metabolismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Células PC12 , Extratos Vegetais/química , Prenilação , Ratos , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A new iridoid glycoside, named 6'-O-trans-feruloyl-8-epiloganic acid, together with fifteen known compounds were isolated from the twigs and leaves of Callicarpa nudiflora, a traditional Chinese medicine to treat inflammatory-related diseases. Their structures were identified by comprehensive spectroscopic analysis and comparison with reported data. Bioassay results revealed that twelve of the isolates could obviously inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 cell lines with IC50 values from 0.64 to 38.72â µM. Among them, compounds 1 (3.27â µM), 6 (5.23â µM), 13 (1.56â µM) and 14 (0.64â µM) exhibited significantly higher activities than that of the positive control (27.13â µM). Additionally, it was supposed that the presence of the carboxy group at the C-4 position of iridoid glycosides and glycosylation at C-3 position of flavonoids might impact their inhibitory activities against NO production.
Assuntos
Callicarpa , Glicosídeos Iridoides , Glicosídeos Iridoides/farmacologia , Glicosídeos Iridoides/química , Callicarpa/química , Flavonoides/farmacologia , Estrutura Molecular , Glicosídeos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Óxido NítricoRESUMO
Four highly oxygenated sesquiterpenoids, illimicranolides A (1) and B (2), and illicinolides E (3) and F (4), were obtained from the fruits of Illicium micranthum Dunn, as well as one known analog, illicinolide B (5). The chemical structures of 1-4 were determined comprehensively by 1D (1 H and 13 C) and 2D (HMBC, HSQC, 1 H-1 H COSY, and ROESY) NMR, and HR-ESI-MS data. Structurally, compound 1 was an unprecedented sesquiterpenoid with a 5/5/6/5-fused tetracyclic ring system and was the first seco-prezizaane sesquiterpenoid featuring a 11,8-γ-lactone ring. Compounds 3 and 4 were the fifth and sixth examples of illicinolide-type sesquiterpenoids. Moreover, compound 1 demonstrated neurotrophic activity of NGF-induced PC12 cells with differentiation rate of 10.34 % at a concentration of 10⠵M.
Assuntos
Illicium , Sesquiterpenos , Animais , Frutas , Illicium/química , Lactonas/química , Estrutura Molecular , Ratos , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
Seven new labdane diterpenoids, hypopurolides A-G (1-7) were discovered from the aerial part of Hypoestes purpurea, along with one known analog, hypopurin D (8). The structures of 1-7 were characterized based on 1 H-, 13 C-, and 2D-NMR, and HR-ESI-MS spectra. The absolute configurations of 1-7 were defined by single-crystal X-ray diffraction and electronic circular dichroism (ECD) data. Compounds 1-8 were tested for their nitric oxide (NO) inhibitory and cytotoxic effects. Compound 6 displayed moderate inhibitory effect toward LPS-induced NO release in RAW 264.7 cells with an IC50 value of 41.50â µM.
Assuntos
Acanthaceae , Diterpenos , Acanthaceae/química , Animais , Diterpenos/química , Diterpenos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico , Células RAW 264.7RESUMO
KGP94 is a potent, selective, and competitive inhibitor of the lysosomal endopeptidase enzyme (Cathepsin L) currently in preclinical trials for the treatment of metastatic cancer, which is a leading cause of cancer-associated death. Herein, we report two new synthetic routes for synthesizing the target compound through four consecutive steps, using a Weinreb amide approach starting from a common 3-bromobenzoyl chloride. A key step in the approach is a coupling reaction of a readily available Grignard reagent with amide 4 to produce 6, a previously unreported coupling pattern. These new strategies offer an efficient and alternative approach to synthesis of target compound with an excellent overall yield.
Assuntos
Catepsina L/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Tiossemicarbazonas/farmacologia , Tioureia/análogos & derivados , Catepsina L/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Tioureia/síntese química , Tioureia/química , Tioureia/farmacologiaRESUMO
Pseudolaric acid A (PAA), one of the main bioactive ingredients in traditional medicine Pseudolarix cortex, exhibits remarkable anticancer activities. Yet its mechanism of action and molecular target have not been investigated and remain unclear. In this work, mechanistic study showed that PAA induced cell cycle arrest at G2/M phase and promoted cell death through caspase-8/caspase-3 pathway, demonstrating potent antiproliferation and anticancer activities. PAA was discovered to be a new Hsp90 inhibitor and multiple biophysical experiments confirmed that PAA directly bind to Hsp90. Active PAA-probe was designed, synthesized and biological evaluated. It was subsequently employed to verify the cellular interaction with Hsp90 in HeLa cells through photoaffinity labeling approach. Furthermore, NMR experiments showed that N-terminal domain of Hsp90 and essential groups in PAA are important for the protein-inhibitor recognition. Structure-activity relationship studies revealed the correlation between its Hsp90 inhibitory activity with anticancer activity. This work proposed a potential mechanism involved with the anticancer activity of PAA and will improve the appreciation of PAA as a potential cancer therapy candidate.
Assuntos
Antineoplásicos/farmacologia , Diterpenos/farmacologia , Descoberta de Drogas , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/síntese química , Diterpenos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90/isolamento & purificação , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Two unprecedented tetranorlanostane triterpenoids, poricolides A (1) and B (2), and two new lanostane triterpenoids, 3ß-acetoxy-24-methyllanosta-8,16,24(31)-trien-21-oic acid (3) and 3ß-acetoxylanosta-7,9(11),16,23-tetraen-21-oic acid (4), were isolated from the epidermis of Poria cocos. The structures of 1-4 were determined via analysis of 1 H-, 13 C-, and 2D-NMR, and HR-ESI-MS data, and the absolute configurations of 1 and 3 were established by single-crystal X-ray diffraction analysis. Compounds 1 and 2 were the first report of tetranorlanostane triterpenoid having a δ-lactone ring at C(17). Compounds 3 and 4 were rare lanostane triterpenoids having a double bond between C(16) and C(17). Compounds 1-4 exhibited potent antiproliferative effects against A549, SMMC-7721, MCF-7, and SW480 cancer cell lines with IC50 values from 16.19±0.38 to 27.74±1.12â µM.
Assuntos
Antineoplásicos/farmacologia , Epiderme/química , Triterpenos/farmacologia , Wolfiporia/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
A new neo-clerodane diterpenoid, salvihispin H (1), and six known ones (2-7) were identified from the aerial parts of Salvia hispanica L. The structure and absolute configuration of 1 were elucidated by extensive analysis of spectroscopic (1 H, 13 C, and 2D NMR, and HR-ESI-MS) and single-crystal X-ray diffraction data. The anti-diabetic effects of salvihispin H (1) and salvifaricin (2) were evaluated in diabetic db/db mice. The data showed that 1 and 2 could significantly reduce fasting blood glucose level and improve insulin resistance, and compound 1 exerted glucose-lowering effect more quickly than metformin. In addition, 1 and 2 could also reduce serum TG level in db/db mice. These results demonstrated that compounds 1 and 2 could be considered as potent candidates for the therapy of type 2 diabetes mellitus (T2DM).
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diterpenos Clerodânicos/farmacologia , Hipoglicemiantes/farmacologia , Componentes Aéreos da Planta/química , Salvia/química , Animais , Glicemia/efeitos dos fármacos , Cristalografia por Raios X , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Diterpenos Clerodânicos/química , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura MolecularRESUMO
Catharanthus roseus is a well-known traditional herbal medicine for the treatment of cancer, hypertension, scald, and sore in China. Phytochemical investigation on the twigs and leaves of this species led to the isolation of two new monoterpene indole alkaloids, catharanosines A (1) and B (2), and six known analogues (3-8). Structures of 1 and 2 were established by 1H-, 13C- and 2D-NMR, and HREIMS data. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction analysis. Compound 2 represented an unprecedented aspidosperma-type alkaloid with a 2-piperidinyl moiety at C-10. Compounds 6-8 exhibited remarkable Cav3.1 low voltage-gated calcium channel (LVGCC) inhibitory activity with IC50 values of 11.83 ± 1.02, 14.3 ± 1.20, and 14.54 ± 0.99 µM, respectively.