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1.
Biomed Res Int ; 2020: 5324560, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029513

RESUMO

The ongoing global pandemic caused by the human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions of people and claimed hundreds of thousands of lives. The absence of approved therapeutics to combat this disease threatens the health of all persons on earth and could cause catastrophic damage to society. New drugs are therefore urgently required to bring relief to people everywhere. In addition to repurposing existing drugs, natural products provide an interesting alternative due to their widespread use in all cultures of the world. In this study, alkaloids from Cryptolepis sanguinolenta have been investigated for their ability to inhibit two of the main proteins in SARS-CoV-2, the main protease and the RNA-dependent RNA polymerase, using in silico methods. Molecular docking was used to assess binding potential of the alkaloids to the viral proteins whereas molecular dynamics was used to evaluate stability of the binding event. The results of the study indicate that all 13 alkaloids bind strongly to the main protease and RNA-dependent RNA polymerase with binding energies ranging from -6.7 to -10.6 kcal/mol. In particular, cryptomisrine, cryptospirolepine, cryptoquindoline, and biscryptolepine exhibited very strong inhibitory potential towards both proteins. Results from the molecular dynamics study revealed that a stable protein-ligand complex is formed upon binding. Alkaloids from Cryptolepis sanguinolenta therefore represent a promising class of compounds that could serve as lead compounds in the search for a cure for the corona virus disease.


Assuntos
Alcaloides/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Cryptolepis/química , Pneumonia Viral/tratamento farmacológico , Proteínas Virais/antagonistas & inibidores , Alcaloides/química , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/enzimologia , Simulação por Computador , Infecções por Coronavirus/virologia , Cisteína Endopeptidases , Avaliação Pré-Clínica de Medicamentos , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/virologia , Relação Quantitativa Estrutura-Atividade , Quinolinas/química , Quinolinas/farmacologia , RNA Replicase/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores
2.
J Nat Med ; 74(4): 804-810, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32638295

RESUMO

Two new canthin-6-one alkaloids, 4,9-dimethoxy-5-hydroxycanthin-6-one (1) and 9-methoxy-(R/S)-5-(1-hydroxyethyl)-canthin-6-one (2), together with fifteen known ones were isolated from the roots of Thailand Eurycoma longifolia Jack. Among the known canthin-6-one alkaloids, compounds 9 and 16 were isolated from the Eurycoma genus for the first time. Meanwhile, the nitric oxide (NO) inhibitory activities of all isolates were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 cells at 50 µM. Moreover, a dose-dependent experiment was conducted for active compounds 1, 2, 4, 6, 7, 10, 12-17 at the concentration of 10, 25, and 50 µM, respectively. Consequently, compounds 1, 4, 6, 7, 12, 14, 15, as well as 17 were found to inhibit NO release from RAW264.7 cells in a dose-dependent manner. Two new canthin-6-one alkaloids, 4,9-dimethoxy-5-hydroxycanthin-6-one (1) and 9-methoxy-(R/S)-5-(1-hydroxyethyl)-canthin-6-one (2), together with fifteen known ones were isolated from the roots of Thailand Eurycoma longifolia Jack. Among them, 1, 4, 6, 7, 12, 14, 15, as well as 17 were found to inhibit NO release from RAW264.7 cells in a dose-dependent manner at the concentration of 10, 25, and 50 µM.


Assuntos
Carbolinas/química , Eurycoma/química , Alcaloides Indólicos/química , Extratos Vegetais/química , Raízes de Plantas/química , Tailândia
3.
J Chromatogr A ; 1620: 461036, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32201039

RESUMO

Leaves, flowers, fruits and stems (44 sample groups) were collected from mature Camptotheca acuminate during 2017.3-2018.3 and classified by ultra-high performance liquid chromatography coupled with quadrupole-time of flight-mass spectrometry based metabolomics. One hundred metabolites including forty-seven alkaloids, fifteen terpenes, thirty-two polyphenols and six other metabolites were rapidly identified through the in-house database alignment at first glance. Thirty-three alkaloids classified into five groups including camptothecin group (CG1-13), pumiloside group (PG1-5), strictosidinic acid group (SG1-3), vincosamide group (VG1-7), and a new hybrid group, vincosamide-camptothecin group (VC1-5) were mined and further characterized by MS/MS analyses. The identification of two untapped biosynthetic precursors, 2-hydroxypumiloside (PG2) and 16­hydroxy­15, 16-dihydrocamptothecoside (CG3), along with sixteen new alkaloids enables us for a better understanding of camptothecin biogenetic reasoning. The underlying enzymes involved in camptothecin biosynthesis were also proposed according to the guiding metabolic map, thus purposefully mining of enzymes involved in the downstream biosynthetic pathway of camptothecin could be initiated with the help of this map.


Assuntos
Alcaloides/análise , Vias Biossintéticas , Camptotheca/química , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Camptotecina/análogos & derivados , Camptotecina/análise , Camptotecina/química , Camptotecina/metabolismo , Carbolinas/análise , Carbolinas/química , Bases de Dados como Assunto , Análise Discriminante , Glicosídeos/análise , Glicosídeos/química , Alcaloides Indólicos/análise , Alcaloides Indólicos/química , Análise dos Mínimos Quadrados , Redes e Vias Metabólicas , Metaboloma , Metabolômica , Análise Multivariada , Análise de Componente Principal
4.
Nat Chem Biol ; 16(4): 383-386, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32066966

RESUMO

Cycloaddition reactions generate chemical complexity in a single step. Here we report the crystal structures of three homologous plant-derived cyclases involved in the biosynthesis of iboga and aspidosperma alkaloids. These enzymes act on the same substrate, named angryline, to generate three distinct scaffolds. Mutational analysis reveals how these highly similar enzymes control regio- and stereo-selectivity.


Assuntos
Alcaloides/biossíntese , Aspidosperma/química , Tabernaemontana/química , Alcaloides/química , Carbazóis/química , Reação de Cicloadição/métodos , Alcaloides Indólicos/química , Plantas/química
5.
Chem Pharm Bull (Tokyo) ; 68(2): 117-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009078

RESUMO

The total syntheses of dimeric indole alkaloids, haplophytine, and T988s are described. These dimeric compounds comprising two structurally different indole units are ubiquitous in nature, and many possess pharmaceutically important activities. To realize an efficient chemical synthesis of these dimeric indole alkaloids, the establishment of convergent synthetic strategies and development of new coupling methods are indispensable. The linkage of two highly functionalized units at a late stage of the synthesis frequently induces synthetic problems such as chemoselectivity and steric repulsion. Moreover, although transition metal-catalyzed reactions are usually an effective method for the cross-coupling of two units, the application of these cross-coupling reactions to bond formation involving a sterically hindered C(sp3) is often difficult. Thus, even with precise modern synthetic methods, it is currently difficult to realize convergent syntheses of dimeric indole alkaloids possessing a quaternary carbon linking two units. To combat these synthetic problems, we developed a synthetic method to link two indole units using an Ag-mediated nucleophilic substitution reaction. In this review, we provide a detailed discussion of convergent synthetic strategies and coupling methods for dimeric indole alkaloids.


Assuntos
Técnicas de Química Sintética/métodos , Alcaloides Indólicos/síntese química , Dimerização , Alcaloides Indólicos/química , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo
6.
Alkaloids Chem Biol ; 83: 187-223, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32098650

RESUMO

The tryptamine-derived polycyclic bridged bioactive indole alkaloids subincanadines A-G were isolated in 2002 by Ohsaki and coworkers from the bark of the Brazilian medicinal plant Aspidosperma subincanum. Kobayashi proposed that subincanadines D-F could be biosynthetically resulting from stemmadenine via two different pathways and, furthermore, that the subincanadines A-C could be biogenetically resulting from subincanadines D and E. Kam and coworkers, in their focused efforts, isolated five indole alkaloids from Malaysian Kopsia arborea species, namely valparicine, apparicine, arboridinine, arborisidine, and arbornamine in combination with subincanadine E. On the basis of structural features, it has been proposed and proved in some examples that subincanadine E is a biogenetic precursor of these five different bioactive indole alkaloids bearing complex structural architectures. All important information on isolation, characterization, bioactivity, probable biogenetic pathways, and more specifically racemic and enantioselective total synthesis of subincanadine alkaloids and their biogenetic congeners are summarized in the present chapter. Special importance is given to the total synthesis and the synthetic strategies intended therein, comprising a set of main reactions.


Assuntos
Apocynaceae/química , Alcaloides Indólicos/química , Plantas Medicinais/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/metabolismo , Estrutura Molecular
7.
Molecules ; 25(2)2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31936309

RESUMO

A series of novel 7-substituted-5-(1H-indol-3-yl)tetrazolo[1,5-a]pyrimidine-6-carbonitrile was synthesized via a one-pot, three-multicomponent reaction of appropriate aldehydes, 1H-tetrazole-5-amine and 3-cyanoacetyl indole in catalytic triethylamine. The cytotoxic activity of the new synthesized tetrazolopyrimidine-6-carbonitrile compounds was investigated against HCT-116, MCF-7, MDA-MB-231, A549 human cancer cell lines and one human healthy normal cell line (RPE-1) using the MTT cytotoxicity assay. Compounds 4h, 4b, 4c, 4i and 4a showed potent anticancer activities against human colon cancer. Additionally, all the compounds showed potent anticancer activities on human lung cancer.


Assuntos
Nitrilos/farmacologia , Pirimidinas/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Concentração Inibidora 50 , Nitrilos/síntese química , Nitrilos/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
8.
Planta Med ; 86(2): 96-103, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31777053

RESUMO

Novel immunomodulating agents are currently sought after for the treatment of autoimmune diseases and cancers. In this context, a screening campaign of a collection of 575 cyanobacteria extracts for immunomodulatory effects has been conducted. The screening resulted in several active extracts. Here we report the results of subsequent studies on an extract from the cyanobacterium Hapalosiphon sp. CBT1235. We identified 5 hapalindoles as the compounds responsible for the observed immunomodulatory effect. These indole alkaloids are produced by several strains of the cyanobacterial family Hapalosiphonaceae. They are known for their anti-infective, cytotoxic, and other bioactivities. Modulation of the activity of human immune cells has not yet been described. The immunomodulatory activity of the hapalindoles was characterized in vitro using flow cytometry-based measurements of T cell proliferation after carboxyfluorescein diacetate succinimidyl ester staining, and apoptosis and necrosis induction after annexin V/propidium iodide staining. The most potent compound, hapalindole A, reduced T cell proliferation with an IC50 of 1.56 µM, while relevant levels of apoptosis were measurable only at 10-fold higher concentrations. Hapalindole A-formamide and hapalindole J-formamide, isolated for the first time from a natural source, had much lower activity than the nonformylated derivatives while, at the same time, being less selective for antiproliferative over apoptotic effects.


Assuntos
Proliferação de Células/efeitos dos fármacos , Cianobactérias/química , Fatores Imunológicos/farmacologia , Alcaloides Indólicos/farmacologia , Linfócitos T/efeitos dos fármacos , Adulto , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Estrutura Molecular , Linfócitos T/citologia
9.
Eur J Med Chem ; 187: 111927, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812035

RESUMO

Harmicines constitute novel hybrid compounds that combine two agents with reported antiplasmodial properties, namely ß-carboline harmine and a cinnamic acid derivative (CAD). Cu(I) catalyzed azide-alkyne cycloaddition was employed for the preparation of three classes of hybrid molecules: N-harmicines 6a-i, O-harmicines 7a-i and N,O-bis-harmicines 8a-g,i. In vitro antiplasmodial activities of harmicines against the erythrocytic stage of Plasmodium falciparum (chloroquine-sensitive Pf3D7 and chloroquine-resistant PfDd2 strains) and hepatic stage of P. berghei, as well as cytotoxicity against human liver hepatocellular carcinoma cell line (HepG2), were evaluated. Remarkably, most of the compounds exerted significant activities against both stages of the Plasmodium life cycle. The conjugation of various CADs to harmine resulted in the increased antiplasmodial activity relative to harmine. In general, O-harmicines 7 exhibited the highest activity against the erythrocytic stage of both P. falciparum strains, whereas N,O-bis harmicines 8 showed the most pronounced activity against P. berghei hepatic stages. For the latter compound, molecular dynamics simulations confirmed binding within the ATP binding site of PfHsp90, while the weaker binders, namely 6b and harmine, were found to be positioned away from this structural element. In addition, decomposition of the computed binding free energies into contributions from individual residues suggested guidelines for further derivatization of harmine towards more efficient compounds. Cytotoxicity screening revealed N-harmicines 6 as the least, and O-harmicines 7 as the most toxic compounds. Harmicines 6g, 8b and 6d exerted the most selective action towards Plasmodium over human cells, respectively. These results establish harmicines as hits for future optimisation and development of novel antiplasmodial agents.


Assuntos
Antimaláricos/farmacologia , Cinamatos/farmacologia , Harmina/farmacologia , Alcaloides Indólicos/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Cinamatos/síntese química , Cinamatos/química , Relação Dose-Resposta a Droga , Harmina/síntese química , Harmina/química , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Simulação de Dinâmica Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
10.
Nat Prod Res ; 34(3): 378-384, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30623670

RESUMO

A new prenylated indole alkaloid, named paraherquamide J (1), together with four known compounds (2-5), were isolated from the mangrove rhizosphere soil-derived fungus Penicillium janthinellum HK1-6. The planar structure and relative configuration of 1 were determined by detailed analysis of the spectroscopic data especially the NOESY spectrum. The absolute configuration of 1 was determined by ECD spectra. Compound 2 was first isolated as a natural product and named as paraherquamide K. All isolated metabolites were evaluated for their antibacterial, topoisomerase I (topo I) inhibitory activities and lethality towards brine shrimp Artemia salina.


Assuntos
Antibacterianos/isolamento & purificação , Indolizinas/isolamento & purificação , Penicillium/química , Compostos de Espiro/isolamento & purificação , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Artemia/efeitos dos fármacos , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Indolizinas/toxicidade , Estrutura Molecular , Prenilação , Rizosfera , Compostos de Espiro/toxicidade , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/isolamento & purificação , Inibidores da Topoisomerase I/farmacologia
11.
Planta Med ; 86(1): 19-25, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31663109

RESUMO

Three new (1: -3: ) and 2 known (4: -5: ) bis-indole alkaloids were identified from the bark of Flindersia pimenteliana (Rutaceae). The structures of 1: -3: were elucidated on the basis of their (+)-HRESESIMS and 2D NMR spectroscopic data. Antiplasmodial activity for 1: -3: against chloroquine sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum is also reported, with IC50 values ranging from 0.96 to 2.41 µg/mL. These results expand our knowledge of the structure-activity relationships of potently antiplasmodial isoborreverine-type alkaloids, the bioactivity of which have recently attracted significant attention in the literature.


Assuntos
Antimaláricos/isolamento & purificação , Alcaloides Indólicos/isolamento & purificação , Rutaceae/química , Antimaláricos/química , Antimaláricos/farmacologia , Células HEK293 , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Casca de Planta/química , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade
12.
Nat Commun ; 10(1): 5553, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804483

RESUMO

Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso-Pictet-Spengler cyclization are the key elements to success.


Assuntos
Carbolinas/química , Ciclização , Alcaloides Indólicos/química , Indóis/química , Carbolinas/síntese química , Catálise , Cromatografia Líquida de Alta Pressão , Sinergismo Farmacológico , Alcaloides Indólicos/síntese química , Indóis/síntese química , Modelos Químicos , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Estereoisomerismo
13.
Mar Drugs ; 17(12)2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31817295

RESUMO

Chemical investigation of the secondary metabolites of a rare New Zealand deep-sea sponge, Lamellomorpha strongylata, resulted in the isolation of twenty-one indole alkaloids, including two new bisindoles-(Z)-coscinamide D (1), (E)-coscinamide D (2)-and four compounds isolated for the first time as natural products-lamellomorphamides A (3), B (4), C (5) and D (6). In addition, fifteen previously reported natural products were isolated, seven of which are seco analogs of hamacanthin alkaloids. The one sponge produces enantiomerically pure but opposite configurations of compounds that only differ in the number of bromines, suggesting enantiodivergent biosynthesis. In addition, four compounds were isolated as partial racemates, suggesting these compounds are biosynthesized via two independent routes.


Assuntos
Produtos Biológicos/isolamento & purificação , Alcaloides Indólicos/isolamento & purificação , Poríferos/metabolismo , Animais , Produtos Biológicos/química , Alcaloides Indólicos/química , Nova Zelândia , Metabolismo Secundário , Estereoisomerismo
14.
Molecules ; 24(21)2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31671793

RESUMO

As part of an ongoing program to identify new bioactive compounds from Irish marine bioresources, we selected the subtidal sponge Spongosorites calcicola for chemical study, as fractions of this species displayed interesting cytotoxic bioactivities and chemical profiles. The first chemical investigation of this marine species led to the discovery of two new bisindole alkaloids of the topsentin family, together with six other known indole alkaloids. Missing the usual central core featured by the representatives of these marine natural products, the new metabolites may represent key biosynthetic intermediates for other known bisindoles. These compounds were found to exhibit weak cytotoxic activity against HeLa tumour cells, suggesting a specificity towards previously screened carcinoma and leukaemia cells.


Assuntos
Halogenação , Alcaloides Indólicos/farmacologia , Poríferos/química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Teoria da Densidade Funcional , Células HeLa , Humanos , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Espectroscopia de Prótons por Ressonância Magnética
15.
J Agric Food Chem ; 67(43): 11994-12001, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31618578

RESUMO

Bioactivity-guided isolation of the endophytic fungus Fusarium sambucinum TE-6L residing in Nicotiana tabacum L. led to the discovery of two new angularly prenylated indole alkaloids (PIAs) with pyrano[2,3-g]indole moieties, amoenamide C (1) and sclerotiamide B (2), and four known biosynthetic congeners (3-6). Their structures were determined by comprehensive spectroscopic techniques, electronic circular dichroism (ECD), and X-ray diffraction. Compound 1 containing the bicyclo[2.2.2]diazaoctane core and indoxyl unit is rarely reported. All the compounds were evaluated for their antimicrobial and insecticidal activities. Notably, compounds 1-3 showed potent inhibitory effects against three human- and one plant-pathogenic bacterium, and seven plant-pathogenic fungi. Compounds 2-4 also exhibited remarkable larvicidal activity against first instar larvae of the cotton bollworm Helicoverpa armigera with mortality rates of 70.2%, 83.2%, and 70.5%, respectively. Further toxicity tests on zebrafish embryos were performed to evaluate the potential toxicity of PIAs. Of significance was that compound 3 in particular exhibited the highest activities but the lowest effects on the hatching of embryos among all the compounds. This study provides a basis for understanding developmental toxicity of PIAs exposure to zebrafish embryos, and also indicates the potential environmental risks of other natural compounds exposure in the aquatic ecosystem.


Assuntos
Anti-Infecciosos/química , Endófitos/química , Fusarium/química , Alcaloides Indólicos/química , Inseticidas/química , Animais , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Endófitos/isolamento & purificação , Fungos/efeitos dos fármacos , Fusarium/isolamento & purificação , Alcaloides Indólicos/metabolismo , Alcaloides Indólicos/farmacologia , Inseticidas/metabolismo , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mariposas/efeitos dos fármacos , Tabaco/microbiologia , Peixe-Zebra/embriologia
16.
Nat Chem ; 11(11): 972-980, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31548667

RESUMO

Prenylated indole alkaloids such as the calmodulin-inhibitory malbrancheamides and anthelmintic paraherquamides possess great structural diversity and pharmaceutical utility. Here, we report complete elucidation of the malbrancheamide biosynthetic pathway accomplished through complementary approaches. These include a biomimetic total synthesis to access the natural alkaloid and biosynthetic intermediates in racemic form and in vitro enzymatic reconstitution to provide access to the natural antipode (+)-malbrancheamide. Reductive cleavage of an L-Pro-L-Trp dipeptide from the MalG non-ribosomal peptide synthetase (NRPS) followed by reverse prenylation and a cascade of post-NRPS reactions culminates in an intramolecular [4+2] hetero-Diels-Alder (IMDA) cyclization to furnish the bicyclo[2.2.2]diazaoctane scaffold. Enzymatic assembly of optically pure (+)-premalbrancheamide involves an unexpected zwitterionic intermediate where MalC catalyses enantioselective cycloaddition as a bifunctional NADPH-dependent reductase/Diels-Alderase. The crystal structures of substrate and product complexes together with site-directed mutagenesis and molecular dynamics simulations demonstrate how MalC and PhqE (its homologue from the paraherquamide pathway) catalyse diastereo- and enantioselective cyclization in the construction of this important class of secondary metabolites.


Assuntos
Ascomicetos/química , Alcaloides Indólicos/metabolismo , Oxirredutases/metabolismo , Biocatálise , Reação de Cicloadição , Alcaloides Indólicos/química , Modelos Moleculares , Estrutura Molecular
17.
Phytochemistry ; 168: 112110, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31494345

RESUMO

Based on the occurrence of indole alkaloids in so-called "chloroform leaf surface extracts", it was previously deduced that these alkaloids are present in the cuticle at the leaf surface of Catharanthus roseus and Vinca minor. As no symplastic markers were found in these extracts this deduction seemed to be sound. However, since chloroform is known to destroy biomembranes very rapidly, these data have to be judged with scepticism. We reanalyzed the alleged apoplastic localization of indole alkaloids by employing slightly acidic aqueous surface extracts and comparing the corresponding alkaloid patterns with those of aqueous total leaf extracts. Whereas in the "chloroform leaf surface extracts" all alkaloids are present in the same manner as in the total leaf extracts, no alkaloids occur in the aqueous leaf surface extracts. These results clearly show that chloroform had rapidly destroyed cell integrity, and the related extracts also contain the alkaloids genuinely accumulated within the protoplasm. The related decompartmentation was verified by the massively enhanced concentration of amino acids in aqueous surface extracts of chloroform treated leaves. Furthermore, the chloroform-induced cell disintegration was vividly visualized by confocal laser scanning microscopical analyses, which clearly displayed a strong decrease in the chlorophyll fluorescence in chloroform treated leaves. These findings unequivocally display that the indole alkaloids are not located in the apoplastic space, but exclusively are present symplastically within the cells of V. minor and C. roseus leaves. Accordingly, we have to presume that also other leaf surface extracts employing organic solvents have to be re-investigated.


Assuntos
Catharanthus/química , Alcaloides Indólicos/análise , Alcaloides Indólicos/isolamento & purificação , Extratos Vegetais/análise , Extratos Vegetais/isolamento & purificação , Folhas de Planta/citologia , Vinca/química , Catharanthus/citologia , Alcaloides Indólicos/química , Extratos Vegetais/química , Folhas de Planta/química , Vinca/citologia
18.
Chem Biodivers ; 16(11): e1900349, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31515922

RESUMO

In this work, the antifouling activity of five alkaloids, isolated from trees of the Atlantic rainforest, was studied. The tested alkaloids were olivacine (1), uleine (2) and N-methyltetrahydroellipticine (3) from Aspidosperma australe ('yellow guatambú') and the furoquinoline alkaloids kokusaginine (4) and flindersiamine (5) from Balfourodendron riedelianum ('white guatambú'). All these compounds can be isolated from their natural sources in high yields in a sustainable way. The five compounds were subjected to laboratory tests (attachment test of the mussel Mytilus edulis platensis) and field trials, by incorporation into soluble matrix paints, and 45 days of exposure of the painted panels in the sea. The results show that compound 3 is a very potent antifoulant, and that compounds 4 and 5 are also very active, while compounds 1 and 2 did not show any significant antifouling activity. These results open the way for the development of environmentally friendly antifouling agents, based on abundant and easy-to-purify compounds that can be obtained in a sustainable way.


Assuntos
Aspidosperma/química , Incrustação Biológica/prevenção & controle , Alcaloides Indólicos/farmacologia , Quinolinas/farmacologia , Rutaceae/química , Animais , Bivalves , Brasil , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Quinolinas/química , Quinolinas/isolamento & purificação
19.
Inorg Chem ; 58(20): 13771-13781, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31560525

RESUMO

Cycloclavine is a complex ergot alkaloid containing an unusual cyclopropyl moiety, which has a wide range of biological activities and pharmaceutical applications. The biosynthesis of cycloclavine requires a series of enzymes, one of which is a nonheme FeII/α-ketoglutarate-dependent (aKG) oxidase (Aj_EasH). According to the previous proposal, the cyclopropyl ring formation catalyzed by Aj_EasH follows an unprecedented oxidative mechanism; however, the reaction details are unknown. In this article, on the basis of the recently obtained crystal structure of Aj_EasH (EasH from Aspergillus japonicas), the reactant models were built, and the reaction details were investigated by performing QM-only and combined QM and MM calculations. Our calculation results reveal that the biosynthesis of cyclopropyl moiety involves a radical intermediate rather than a carbocationic or carbanionic intermediate as in the biosynthesis of terpenoid family. The iron(IV)-oxo first abstracts a hydrogen atom from the substrate to trigger the reaction, and then the generated radical intermediate undergoes ring rearrangement to form the fused 5-3 ring system of cycloclavine. On the basis of our calculations, the absolute configuration of the cycloclavine catalyzed by Aj_EasH from Aspergillus japonicus should be (5R,8R,10R), which is different from the product isolated from Ipomoea hildebrandtii (5R,8S,10S). Residues at the active site play an important role in substrate binding, ring rearrangement, and enantioselectivity.


Assuntos
Aspergillus/enzimologia , Alcaloides de Claviceps/biossíntese , Alcaloides Indólicos/metabolismo , Ácidos Cetoglutáricos/metabolismo , Oxirredutases/metabolismo , Biocatálise , Alcaloides de Claviceps/química , Alcaloides Indólicos/química , Ácidos Cetoglutáricos/química , Modelos Moleculares , Conformação Molecular , Oxirredutases/química , Teoria Quântica , Estereoisomerismo
20.
Bol. latinoam. Caribe plantas med. aromát ; 18(5): 527-532, sept. 2019. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1008292

RESUMO

Chemical constituents and biological activities of the aerial parts of Piper erecticaule C.DC. have been studied for the first time. Fractionation and purification of the extracts afforded aristolactam AII (1), aristolactam BII (2), piperolactam A (3), piperolactam C (4), piperolactam D (5), together with terpenoids of ß-sitosterol, ß-sitostenone, taraxerol, and lupeol. The structures of these compounds were obtained by analysis of their spectroscopic data, as well as the comparison with that of reported data. Acetylcholinesterase inhibitory activity revealed that compounds 1 and 3 showed strong AChE inhibitory effects with the percentage inhibition of 75.8% and 74.8%, respectively.


Se estudiaron por primera vez los constituyentes químicos y actividad biológica de las partes aéreas de Piper erecticaule C.DC. El fraccionamiento y la purificación de los extractos proporcionaron aristolactama AII (1), aristolactama BII (2), piperolactama A (3), piperolactama C (4), piperolactama D (5), junto con terpenoides de ß-sitosterol, ß-sitostenona, taraxerol, y el lupeol. Las estructuras de estos compuestos se obtuvieron mediante el análisis de sus datos espectroscópicos, así como mediante la comparación con datos ya informados. La actividad inhibidora de la acetilcolinesterasa reveló que los compuestos 1 y 3 mostraron un potente efecto inhibidor de la AChE con un porcentaje de inhibición del 75.8% y 74.8%, respectivamente.


Assuntos
Aporfinas/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Extratos Vegetais/química , Inibidores da Colinesterase/farmacologia , Piper/química , Alcaloides/farmacologia , Aporfinas/química , Terpenos/isolamento & purificação , Inibidores da Colinesterase/química , Alcaloides Indólicos/química , Alcaloides/química , Lactamas/química
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