RESUMO
Amphidinolides C, F, and U, including C2-C4 analogs, are highly cytotoxic marine macrolides, mainly isolated from dinoflagellates of the genus Amphidinium. All these polyketides share a 75 % or more similar structure, highlighted by a macrolactone ring, at least one trans-2,5-substituted-THF motif and a characteristic polyenic side chain. From their isolation and absolute configurational assignment, the total synthesis of these marine macrolides represented an intense challenge to the organic synthesis community over the last 15â years, with around 14 research groups engaged in this inspiring task. In the first part of this review, we present the different approaches to the isolation and characterization of these natural products, including the most recent analogs, which may cast doubt on the biogenetic origin of these compounds. The various synthetic approaches to the total synthesis of C, F, and U amphidinolides are presented in a second part, focusing on key reactions and/or innovative strategies. The review concludes in a third section summarizing the successful approaches leading to the total synthesis of one of the members of this amphidinolide subfamily.
Assuntos
Produtos Biológicos , Dinoflagellida , Macrolídeos , Macrolídeos/síntese química , Macrolídeos/química , Dinoflagellida/química , Produtos Biológicos/química , Produtos Biológicos/síntese química , Estereoisomerismo , AnfidinolídeosRESUMO
Dengue fever is an infectious disease caused by the dengue virus (DENV), an RNA Flavivirus transmitted by the mosquitoes Aedes aegypti and Aedes albopictus widespread in tropical, subtropical and also temperate regions. Symptoms range from a simple cold to a severe, life-threatening haemorrhagic fever. According to the WHO, it affects around 390 million people per year. No antiviral treatment for DENV is available, and the Dengvaxia vaccine is only intended for people over 9 years of age who have contracted dengue one time in the past, and shows serotype-specific effectiveness. There is therefore a crying need to discover new molecules with antiviral power against flaviviruses. The present study was carried out to evaluate the anti-DENV activities and cytotoxicity of triazenes obtained by diazocopulation. Some triazenes were highly cytotoxic (16, and 25) to hepatocarcinoma Huh7 cells, whereas others displayed strong anti-DENV potential. The antiviral activity ranged from EC50 = 7.82 µM to 48.12 µM in cellulo, with a selectivity index (CC50/EC50) greater than 9 for two of the compounds (10, and 20). In conclusion, these new triazenes could serve as a lead to develop and optimize drugs against DENV.
Assuntos
Aedes , Vírus da Dengue , Dengue , Animais , Humanos , Dengue/tratamento farmacológico , Antivirais/farmacologiaRESUMO
Amphidinolides F, C, C2, and C3 are marine natural products isolated from dinoflagellates Amphidinium species. They share the same macrolactone core, with the difference between them residing at the side chain level. A predominant feature of these amphidinolides is the presence of two trans-THF rings inside the macrolactone core, which is thought to be built by C-glycosylation with titanium enolate of N-acetyl oxazolinethiones. Thus, the original strategy for their total synthesis was based on the assembly of three main fragments corresponding to C1-C9, C10-C19, and C20-C29 or C20-C34 disconnections. Whereas synthesis of all fragments was successful, the C-glycosylation reaction between C19 and C20 turned out to be an issue. Therefore, a second route was designed. The new disconnection between C17 and C18 was based on a sulfone addition and a desulfonylation sequence. Our convergent strategy allowed the total synthesis of amphidinolide F and enabled a new unifying route toward the synthesis of amphidinolides C, C2, and C3 using a late-stage divergent approach. Although there were unsatisfying yields at some critical steps, our work culminated into the first total synthesis of amphidinolide C2.
Assuntos
Produtos Biológicos , Dinoflagellida , Macrolídeos , Estrutura Molecular , EstereoisomerismoRESUMO
Dengue fever, caused by dengue virus (DENV), is the most prevalent arthropod-borne viral disease and is endemic in many tropical and subtropical parts of the world, with an increasing incidence in temperate regions. The closely related flavivirus Zika virus (ZIKV) can be transmitted vertically in utero and causes congenital Zika syndrome and other birth defects. In adults, ZIKV is associated with Guillain-Barré syndrome. There are no approved antiviral therapies against either virus. Effective antiviral compounds are urgently needed. Amaryllidaceae alkaloids (AAs) are a specific class of nitrogen-containing compounds produced by plants of the Amaryllidaceae family with numerous biological activities. Recently, the AA lycorine was shown to present strong antiflaviviral properties. Previously, we demonstrated that Crinum jagus contained lycorine and several alkaloids of the cherylline, crinine, and galanthamine types with unknown antiviral potential. In this study, we explored their biological activities. We show that C. jagus crude alkaloid extract inhibited DENV infection. Among the purified AAs, cherylline efficiently inhibited both DENV (50% effective concentration [EC50], 8.8 µM) and ZIKV replication (EC50, 20.3 µM) but had no effect on HIV-1 infection. Time-of-drug-addition and -removal experiments identified a postentry step as the one targeted by cherylline. Consistently, using subgenomic replicons and replication-defective genomes, we demonstrate that cherylline specifically hinders the viral RNA synthesis step but not viral translation. In conclusion, AAs are an underestimated source of antiflavivirus compounds, including the effective inhibitor cherylline, which could be optimized for new therapeutic approaches.
Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Vírus da Dengue , Dengue , Infecção por Zika virus , Zika virus , Adulto , Alcaloides/farmacologia , Alcaloides de Amaryllidaceae/farmacologia , Humanos , Isoquinolinas , Replicação Viral , Infecção por Zika virus/tratamento farmacológicoRESUMO
Amaryllidaceae plants are rich in alkaloids with biological properties. Pancratium trianthum is an Amaryllidaceae species widely used in African folk medicine to treat several diseases such as central nervous system disorders, tumors, and microbial infections, and it is used to heal wounds. The current investigation explored the biological properties of alkaloid extracts from bulbs of P. trianthum collected in the Senegalese flora. Alkaloid extracts were analyzed and identified by chromatography and mass spectrometry. Alkaloid extracts from P. trianthum displayed pleiotropic biological properties. Cytotoxic activity of the extracts was determined on hepatocarcinoma Huh7 cells and on acute monocytic leukemia THP-1 cells, while agar diffusion and microdilution assays were used to evaluate antibacterial activity. Antiviral activity was measured by infection of extract-treated cells with dengue virus (DENVGFP) and human immunodeficiency virus-1 (HIV-1GFP) reporter vectors. Cytotoxicity and viral inhibition were the most striking of P. trianthum's extract activities. Importantly, non-cytotoxic concentrations were highly effective in completely preventing DENVGFP replication and in reducing pseudotyped HIV-1GFP infection levels. Our results show that P. trianthum is a rich source of molecules for the potential discovery of new treatments against various diseases. Herein, we provide scientific evidence to rationalize the traditional uses of P. trianthum for wound treatment as an anti-dermatosis and antiseptic agent.
Assuntos
Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Amaryllidaceae/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Linhagem Celular Tumoral , Dengue/tratamento farmacológico , Vírus da Dengue/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
The seeds of Carapa procera are exploited extensively in West African ethnopharmacy for the treatment of several pathologies, including inflammation. They also are effective as insect antifeedants and as a mosquito repellent. With the aim of identifying bioactive principles, an ethyl acetate extract of the defatted seeds was made and fractionated. Two principle compounds were isolated. One of these, 5,6-dehydro-7-deacetoxy-7-oxogedunin (1), while known from another genus of the Meliaceae, is newly identified from the genus Carapa and its X-ray structure is described for the first time. In addition, 1 displayed strong anti-clonogenic activity at 10 µM. The other compound, mexicanolide (2), is known from this species and showed neither cytotoxicity nor anti-clonogenicity. These differences in efficacy are discussed in relation to known structure-activity relationships of limonoids.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Limoninas/isolamento & purificação , Meliaceae/química , Extratos Vegetais/isolamento & purificação , Triterpenos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Limoninas/química , Limoninas/farmacologia , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sementes/química , Triterpenos/química , Triterpenos/farmacologiaRESUMO
In the title compound, C17H18N4O5·0.47CH3OH, the virtually planar (r.m.s. deviation = 0.128â Å) carbonohydrazide mol-ecule is located on a twofold axis and conformation of its C=N bonds is E. There are short intra-molecular O-Hâ¯N hydrogen bonds between the hy-droxy groups and hydrazide N atoms. In the crystal, bifurcated N-Hâ¯(O,O) hydrogen bonds assemble the carbonohydrazide mol-ecules into a three-dimensional network. There are C 2 symmetric voids in this network, 47% of which are occupied by disordered methanol mol-ecules.
RESUMO
Natural products (NPs) are endless sources of compounds for fighting against several pathologies. Many dysfunctions, including cardiovascular disorders, such as cardiac arrhythmias have their modes of action regulation of the concentration of electrolytes inside and outside the cell targeting ion channels. Here, we highlight plant extracts and secondary metabolites' effects on the treatment of related cardiac pathologies on hERG, Nav, and Cav of cardiomyocytes. The natural product's pharmacology of expressed receptors like alpha-adrenergic receptors causes an influx of Ca2+ ions through receptor-operated Ca2+ ion channels. We also examine the NPs associated with cardiac contractions such as myocardial contractility by reducing the L-type calcium current and decreasing the intracellular calcium transient, inhibiting the K+ induced contractions, decreasing amplitude of myocyte shortening and showed negative ionotropic and chronotropic effects due to decreasing cytosolic Ca2+. We examine whether the NPs block potassium channels, particular the hERG channel and regulatory effects on Nav1.7.
RESUMO
The study aimed to investigate the chemical composition and antimicrobial and antioxidant activities of the essential oil from dried seeds of Xylopia aethiopica. The essential oil was obtained by hydrodistillation and analyzed by GC/FID and GC/MS. The essential oil yield was 1.35%. Forty-nine compounds were identified in the essential oil with 1,8-cineole (16.3%), ß-pinene (14.8%), trans-pinocarveol (9.1%), myrtenol (8.3%), α-pinene (5.9%), and terpinen-4-ol (5.6%) as major components. The antimicrobial activity of this essential oil was studied using disk diffusion and broth microdilution methods on four bacteria (Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa) and one fungus (Candida albicans). The essential oil exhibited excellent activity against S. aureus, E. faecalis, and C. albicans and moderate activity against E. coli. Among all strains tested, C. albicans showed the best sensitivity with a MIC of 50 mg/mL. The antioxidant activity was examined using a DPPH-free radical scavenging assay. The essential oil of X. aethiopica showed low antioxidant activity (IC50 = 784.604 ± 0.320 mg/mL) compared to that of ascorbic acid and the reference compound (IC50 = 0.163 ± 0.003 mg/mL). The results indicate that consumption of X. aethiopica seeds can reduce the virulence of food-borne pathogens and their resistance to antibiotics.
RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: In Senegal, upper and lower respiratory tract infections constitute a real health problem. To manage these disorders, most people rely on the use of local medicinal plants. This is particularly the case for species belonging to the botanical families, Combretaceae, Fabaceae, Myrtaceae and Rubiaceae, which are widely used to treat various respiratory problems such as colds, flu, rhinitis, sinusitis, otitis, angina, bronchitis, bronchiolitis and also pneumonia. AIM OF THE STUDY: The aim of this study was to identify medicinal plants traditionally used for the management of infectious diseases, in particular those of the respiratory tract. On the basis of these ethnopharmacological uses, this study made it possible to highlight the antibacterial, antiviral and cytotoxic activities of selected plant species. MATERIALS AND METHODS: An ethnobotanical survey was conducted in Senegal among informants, including herbalists, traditional healers, and households, using medicinal plants in the management of infectious diseases, with a focus on respiratory tract infections. The most cited plant species were evaluated in vitro on a panel of 18 human pathogenic bacteria may be involved in respiratory infections and against the human coronavirus HCoV-229E in Huh-7 cells. The antiviral activity of the most active extracts against HCoV-229E was also evaluated on COVID-19 causing agent, SARS-CoV-2 in Vero-81 cells. In parallel, cytotoxic activities were evaluated on Huh-7 cells. RESULTS: A total of 127 informants, including 100 men (78.74%) and 27 women (21.26%) participated in this study. The ethnobotanical survey led to the inventory of 41 plant species belonging to 19 botanical families used by herbalists and/or traditional healers and some households to treat infectious diseases, with a specific focus on upper respiratory tract disorders. Among the 41 plant species, the most frequently mentioned in the survey were Guiera senegalensis J.F. Gmel. (95.2%), Combretum glutinosum Perr. Ex DC. (93.9%) and Eucalyptus spp. (82.8%). Combretaceae (30.2%) represented the most cited botanical family with six species, followed by Fabaceae (29.3%, 12 species). A total of 33 crude methanolic extracts of the 24 plant species selected for their number of citations were evaluated in vitro for their antimicrobial and cytotoxic activities. Guiera senegalensis, Combretum glutinosum, Vachellia nilotica subsp. tomentosa (Benth.) Kyal. & Boatwr, Eucalyptus camaldulensis Dehnh., and Terminalia avicennioides Guill. & Perr., showed antibacterial activities. The most active plants against HCoV-229E were: Ficus sycomorus L., Mitragyna inermis (Willd.) Kuntze, Pterocarpus erinaceus Poir., and Spermacoce verticillata L. One of these plants, Mitragyna inermis, was also active against SARS-CoV-2. CONCLUSION: This work confirmed the anti-infective properties of plant species traditionally used in Senegal. Overall, the most frequently cited plant species showed the best antibacterial activities. Moreover, some of the selected plant species could be considered as a potential source for the management of coronavirus infections. This new scientific data justified the use of these plants in the management of some infectious pathologies, especially those of the respiratory tract.
Assuntos
Anti-Infecciosos , COVID-19 , Combretaceae , Combretum , Doenças Transmissíveis , Coronavirus Humano 229E , Plantas Medicinais , Masculino , Humanos , Feminino , Fitoterapia , Medicinas Tradicionais Africanas , Etnobotânica , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/uso terapêutico , Doenças Transmissíveis/tratamento farmacológicoRESUMO
Two new heterocyclic 1,2,3-triazenes were synthesized by diazo-tation of 3-amino-pyridine following respectively by coupling with morpholine or 1,2,3,4-tetra-hydro-quinoline. 4-[(Pyridin-3-yl)diazen-yl]morpholine (I), C9H12N4O, has monoclinic P21/c symmetry at 100â K, while 1-[(pyridin-3-yl)diazen-yl]-1,2,3,4-tetra-hydro-quinoline (II), C14H14N4, has monoclinic P21/n symmetry at 100â K. These 1,2,3-triazene derivatives were synthesized by the organic medium method by coupling reactions of 3-amino-pyridine with morpholine and 1,2,3,4-tetra-hydro-quinoline, respectively, and characterized by 1H NMR, 13C NMR, IR, mass spectrometry, and single-crystal X-ray diffraction. The mol-ecule of compound I consists of pyridine and morpholine rings connected by an azo moiety (-N=N-). In the mol-ecule of II, the pyridine ring and the 1,2,3,4-tetra-hydro-quinoline unit are also connected by an azo moiety. The double- and single-bond distances in the triazene chain are comparable for the two compounds. In both crystal structures, the mol-ecules are connected by C-Hâ¯N inter-actions, forming infinite chains for I and layers parallel to the bc plane for II.
RESUMO
Crinum biflorum Rottb. (syn. Crinum distichum) is an Amaryllidaceae plant used in African traditional medicine but very few studies have been performed on this species from a chemical and applicative point of view. Bulbs of C. biflorum, collected in Senegal, were extracted with ethanol by Soxhlet and the corresponding organic extract was purified using chromatographic methods. The pure compounds were chemically characterized by spectroscopic techniques (1D and 2D 1H and 13C NMR, HR MS and ECD) and X-ray analysis. Four homoisoflavonoids (1-4) and one alkylamide (5) were isolated and characterized as 5,6,7-trimethoxy-3-(4-hydroxybenzyl)chroman-4-one (1), as 3-hydroxy-5,6,7-trimethoxy-3-(4-hydroxybenzyl)chroman-4-one (2), as 3-hydroxy-5,6,7-trimethoxy-3-(4-methoxybenzyl)chroman-4-one (3) and as 5,6,7-trimethoxy-3-(4-methoxybenzyl)chroman-4-one (4), and the alkylamide as (E)-N-(4-hydroxyphenethyl)-3-(4-hydroxyphenyl)acrylamide (5), commonly named N-p-coumaroyltyramine. The relative configuration of compound 1 was verified thanks to the X-ray analysis which also allowed us to confirm its racemic nature. The absolute configurations of compounds 2 and 3 were assigned by comparing their ECD spectra with those previously reported for urgineanins A and B. Flavanoids 1, 3 and 4 showed promising anticancer properties being cytotoxic at low micromolar concentrations towards HeLa and A431 human cancer cell lines. The N-p-coumaroyltyramine (5) was selectively toxic to A431 and HeLa cancer cells while it protected immortalized HaCaT cells against oxidative stress induced by hydrogen peroxide. Compounds 1-4 also inhibited acetylcholinesterase activity with compound 3 being the most potent. The anti-amylase and the strong anti-glucosidase activity of compound 5 were confirmed. Our results show that C. biflorum produces compounds of therapeutic interest with anti-diabetic, anti-tumoral and anti-acetylcholinesterase properties.
Assuntos
Amaryllidaceae/química , Ácidos Cumáricos/isolamento & purificação , Crinum/química , Flavonoides/isolamento & purificação , Acetilcolinesterase/metabolismo , Antivirais/farmacologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Ácidos Cumáricos/química , Flavonoides/química , Fluoresceínas/metabolismo , HIV-1/efeitos dos fármacos , Células HaCaT , Células HeLa , Humanos , Hipoglicemiantes/farmacologia , Metaboloma , Conformação Molecular , Senegal , alfa-Amilases/metabolismoRESUMO
Three undescribed Amarylidaceae alkaloids, named gigantelline, gigantellinine and gigancrinine, were isolated from Crinum jagus (syn.â¯=â¯Crinum giganteum) collected in Senegal, together with the already known sanguinine, cherylline, lycorine, crinine, flexinine and the isoquinolinone derivative hippadine. Gigantelline, gigantellinine and gigancrinine were characterized as 4-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenol, its 7-O-demethyl-5ê-hydroxy-4ê-methoxy derivative and 5,6a,7,7a,8a,9-hexahydro-6,9a-ethano[1,3]dioxolo[4,5-j]oxireno[2,3-b]phenanthridin-9-ol, respectively, by using spectroscopic (1D and 2D 1H and 13C NMR and HRESIMS) and chemical methods. Their relative configuration was assigned by NOESY NMR spectra and NMR calculations, while the absolute configuration was assigned using electronic circular dichroism (ECD) experiments and calculations. Sanguinine, cherylline, crinine, flexinine, and the isoquinolinone hippadine, were isolated for the first time from C. jagus. Cherylline, gigantellinine, crinine, flexinine and sanguinine inhibited the activity of AChE in a dose-dependent manner, and inhibition by sanguinine was remarkably effective (IC50â¯=â¯1.83⯱â¯0.01⯵M). Cherylline and hippadine showed weak cytotoxicity at 100⯵M.
Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Crinum , Isoquinolinas , Estrutura MolecularRESUMO
BACKGROUND: Due to the rapid development of microbial resistance, finding new molecules became urgent to counteract this problem. OBJECTIVE: The objective of this work is to access 1,2,3-triazene-1,3-disubstituted, a class of molecule with high therapeutic potential. METHODS: Here we describe the access to 17 new triazene including six with an imidazole-1,2,3-triazene moiety and eleven with an alkyl-1,2,3-triazene moiety and their evaluation against five strains: two gram (-): Escherichia coli ATCC 25921 and Pseudomonas aeruginosa ATCC 27253; two gram (+) : Staphylococcus aureus ATCC 38213 and Enterococcus faecalis ATCC 29212; and one fungi: Candida albicans ATCC 24433. RESULTS: All strains were sensitive and the best MIC, 0.28 µM, is observed for 4c against Escherichia coli ATCC 25921. Compound 9, 3-isopropynyltriazene, appears to be the most interesting since it is active on the five evaluated strains with satisfactory MIC 0.32 µM against Escherichia coli and Pseudomonas aeruginosa and 0.64 µM against Enterococcus faecalis and Pseudomonas aeruginosa. CONCLUSION: Comparing the structure activity relationship, electron withdrawing groups appear to increase antimicrobial activity.
Assuntos
Anti-Infecciosos/química , Bibliotecas de Moléculas Pequenas/química , Triazenos/química , Candida albicans/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Enterococcus faecalis/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Triazenos/farmacologiaRESUMO
trans-2,5-Disubstituted tetrahydrofurans were obtained as major diastereomers (trans/cis ratio 90:10-100:0) when acetylated gamma-lactols derived from (S)-glutamic acid were treated with titanium enolates of N-acetyl (R)-oxazolidin-2-thiones. A simple transesterification allowed us to obtain the corresponding methyl esters and recover the chiral auxiliary.