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1.
Alkaloids Chem Biol ; 86: 1-143, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34565505

RESUMO

Of Nature's nearly 3000 unique monoterpene indole alkaloids derived from tryptophan, those members belonging to the Aspidosperma and Strychnos families continue to impact the fields of natural products (i.e., isolation, structure determination, biosynthesis) and organic chemistry (i.e., chemical synthesis, methodology development) among others. This review covers the biological activity (Section 2), biosynthesis (Section 3), and synthesis of both classical and novel Aspidosperma (Section 4), Strychnos (Section 5), and selected bis-indole (Section 6) alkaloids. Technological advancements in genetic sequencing and bioinformatics have deepened our understanding of how Nature assembles these intriguing molecules. The proliferation of innovative synthetic strategies and tactics for the synthesis of the alkaloids covered in this review, which include contributions from over fifty research groups from around the world, are a testament to the creative power and technical skills of synthetic organic chemists. To be sure, Nature-the Supreme molecular architect and source of a dazzling array of irresistible chemical logic puzzles-continues to inspire scientists across multiple disciplines and will certainly continue to do so for the foreseeable future.


Assuntos
Alcaloides , Aspidosperma , Strychnos , Biologia , Humanos , Alcaloides Indólicos
2.
Arch Microbiol ; 203(7): 4663-4675, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34175964

RESUMO

Quorum sensing (QS) represents a major target for reducing bacterial pathogenicity and antibiotic resistance. This study identifies bergamot and aspidosperma as new potential sources of anti-QS agents. We investigated the anti-QS activity of plant materials on both Chromobacterium violaceum and Pseudomonas aeruginosa. Initially, we determined the minimum inhibitory concentrations (MICs) of plant materials using a broth microdilution method. Subsequently, we tested the effect of sub-MIC concentrations on QS-regulated traits and virulence factors production in test bacteria. Results revealed that bergamot and aspidosperma inhibited the ability of C. violaceum to produce violacein. Other QS-controlled phenotypes of C. violaceum, namely chitinolytic activity, motility, and biofilm formation, were also reduced by both plant materials. Moreover, QS-linked traits of P. aeruginosa were also reduced. Bergamot inhibited swarming but not swimming motility, while aspidosperma diminished both motility types in P. aeruginosa. Both plant materials also demonstrated antibiofilm activity and inhibited the production of protease and pyocyanin in P. aeruginosa. Furthermore, we tested the anti-QS effect of plant materials on the transcriptional level using RT-qPCR. Bergamot dramatically downregulated the C. violaceum autoinducer synthase gene cviI and the vioB gene involved in violacein biosynthesis, confirming the phenotypic observation on its anti-QS activity. Aspidosperma also reduced the expression of cviI and vioB but less drastically than bergamot. In P. aeruginosa, downregulation in the transcripts of the QS genes lasI, lasR, rhlI, and rhlR was also achieved by bergamot and aspidosperma. Therefore, data in the present study suggest the usefulness of bergamot and aspidosperma as sources of antivirulence agents.


Assuntos
Aspidosperma , Chromobacterium , Extratos Vegetais , Óleos Vegetais , Pseudomonas aeruginosa , Percepção de Quorum , Antibacterianos/farmacologia , Aspidosperma/química , Biofilmes/efeitos dos fármacos , Chromobacterium/efeitos dos fármacos , Chromobacterium/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Extratos Vegetais/farmacologia , Óleos Vegetais/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Percepção de Quorum/efeitos dos fármacos , Percepção de Quorum/genética , Fatores de Virulência/genética
3.
Phytochemistry ; 184: 112673, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33556841

RESUMO

The Melodinus species have been proved to be good resources of bisindole alkaloids. Six bisindole alkaloids were isolated from the leaves and stems of Melodinus cochinchinensis (Lour.) Merr. guided by HRESIMS data analysis. Among them, melokhanines K-M, epi-scandomelonine, and epi-scandomeline possessed aspidosperma-scandine skeleton linked by a C-C bond while meloyine II had a scandine-scandine skeleton. The structures were established by extensive spectroscopic analysis of their HRESIMS and NMR data. Melokhanines K-M were undescribed compounds, while epi-scandomelonine, epi-scandomeline and meloyine II were known compounds, which were reported from Melodinus species for the first time. The anti-inflammatory and cytotoxic activities of the isolates were also evaluated in vitro. Melokhanine K and meloyine II showed potent inhibitory activity on the production of nitric oxide, interleukin-6, and tumor necrosis factor-α in LPS-induced RAW 264.7 macrophages, whereas epi-scandomelonine and epi-scandomeline exhibited certain cytotoxic activity against MOLT-4 cells with IC50 values 5.2 and 1.5 µM, respectively.


Assuntos
Alcaloides , Apocynaceae , Aspidosperma , Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Alcaloides Indólicos/farmacologia , Estrutura Molecular
4.
Phytochemistry ; 181: 112566, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33197743

RESUMO

Fourteen undescribed monoterpenoid indole alkaloids, voacafrines A-N, along with 7 known monoterpenoid indole alkaloids were isolated from the seeds of Voacanga africana Stapf. Among them, voacafrines A-G were aspidosperma-aspidosperma type bisindole alkaloids, while voacafrines H-N were aspidosperma-type monomers. Their structures and absolute configurations were elucidated by a combination of NMR, MS, and ECD analyses. Voacafrines A-C were characterized by an acetonyl moiety at C-5', while voacafrine H possessed a methoxymethyl moiety at C-14 within aspidosperma-type alkaloids. The acetylcholinesterase (AChE) inhibitory activity and cytotoxicity of voacafrines A-N were evaluated. Voacafrines A-C and E-G were bisindole alkaloids that exhibited AChE inhibitory activity with IC50 values of 4.97-33.28 µM, while voacafrines I and J were monomers that showed cytotoxicity against several human cancer cell lines with IC50 values of 4.45-7.49 µM.


Assuntos
Aspidosperma , Alcaloides de Triptamina e Secologanina , Voacanga , Alcaloides Indólicos/farmacologia , Estrutura Molecular , Alcaloides de Triptamina e Secologanina/farmacologia
5.
J Org Chem ; 85(23): 14817-14826, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33205969

RESUMO

Herein, the first total syntheses of (-)-pseudocopsinine (1) and (-)-minovincine (3) from a common intermediate 8 are detailed, enlisting late-stage, hydrogen atom transfer (HAT)-mediated free radical bond formations (C20-C2 and C20-OH, respectively) that are unique to their core or structure. The approach to 1 features an Fe-mediated HAT reaction of the intermediate olefin 2, effecting a transannular C20-C2 free radical cyclization of a challenging substrate with formation of a strained [2.2.1] ring system and reaction of a poor acceptor tetrasubstituted alkene with a hindered secondary free radical to form a bond and quaternary center adjacent to another quaternary center. Central to the assemblage of their underlying Aspidosperma skeleton is a powerful [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazole 9, which affords the stereochemically rich and highly functionalized pentacyclic intermediate 8 as a single diastereomer in one step. The work extends the divergent total synthesis of four to now six different natural product alkaloid classes by distinguishing late stage key strategic bond formations within the underlying Aspidosperma core from the common intermediate 8. Together, the work represents use of strategic bond analysis combined with the strategy of divergent synthesis to access six different natural product classes from a single intermediate.


Assuntos
Aspidosperma , Ciclização , Reação de Cicloadição , Estrutura Molecular , Estereoisomerismo
6.
An Acad Bras Cienc ; 92(suppl 2): e20181002, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33084750

RESUMO

The structural complexity of galls depends on species-specific interaction driven by the galling taxa. However, the host plant and environment stressors can impose limits on gall developmental patterns and impact the establishment of gall morphology. Herein, we employed qualitative and quantitative approaches in order to elucidate how cell divisions, elongation patterns, and tissue organization are determinant for the development of intralaminar gall morphology induced by Pseudophacopteron longicaudatum Malenovský, Burckhardt, Queiroz, Isaias & Oliveira (Hemiptera: Psylloidea: Phacopteronidae) on leaves of Aspidosperma tomentosum Mart. (Apocynaceae). In addition, we aimed to determine which anatomical process can discriminate the stages of gall development, plus, examine the histochemical and cytological profiles of the galls. The differentiated structures, mainly abaxial epidermis and spongy parenchyma, are associated with gall closure, with hyperplastic events concentrated in the young phase of the galls. Thus, epidermis and spongy parenchyma hypertrophy and are responsible for the determination of the nymphal chamber formation and gall shape. The mature galls do not differentiate into a typical nutritive cells and do not develop a histochemical gradient in their tissues. The cytological features of galls such as plastoglobules and multivesicular bodies are related to ROS scavenging mechanisms due the high oxidative stress.


Assuntos
Apocynaceae , Aspidosperma , Hemípteros , Animais , Folhas de Planta , Tumores de Planta
7.
Forensic Sci Int ; 314: 110371, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32623089

RESUMO

Plant DNA barcoding has proven to be a handy tool for identifying botanical species. However, extracting DNA from woody materials is often a challenging task. Forensic applications, therefore, must be able to overcome the technical difficulties of this nature. A simple and successful adaptation, through a widely used method in forensic laboratories, using chemistry based on magnetic DNA isolation technology and a robotic platform, is presented here. The model case was the application of this adapted DNA extraction method for the identification of Aspidosperma spp., a genus comprising several species in all biomes of Brazil, including Cerrado and Rain Forest. Such technology adaptation can aid in the identification of seized material and help in investigations involving illegal logging and deforestation, ultimately contributing to environmental protection.


Assuntos
Aspidosperma/genética , DNA de Plantas/isolamento & purificação , Madeira/genética , Brasil , Conservação dos Recursos Naturais , Bases de Dados de Ácidos Nucleicos , Genética Forense/métodos , Humanos , Projetos Piloto , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Especificidade da Espécie , Manejo de Espécimes/métodos
8.
Molecules ; 25(11)2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32481577

RESUMO

Olivacine is an alkaloid-containing pyridocarbazole structure. It is isolated from the bark of the evergreen timber tree, Aspidosperma olivaceum. Its well-documented anticancer activity led to the synthesis of new derivatives, which are semisynthetic and fully synthetic pyridocarbazoles. This study aimed to evaluate the potential antineoplastic activity of four newly synthesized olivacine derivatives. Multidrug resistance is a common phenomenon causing failure in the chemotherapy of many tumors. It is mainly related to increased function of P-glycoprotein, an efflux pump removing cytostatic out of the cells. The cell lines used in the study were colorectal carcinoma cell lines: LoVo (doxorubicin-sensitive) and LoVo/DX (doxorubicin-resistant). The NHDF cell line was used to assess cell viability. First, the cells were incubated with olivacine derivatives. In the next step, the following assays were performed: DCF-DA assay, MTT assay, rhodamine 123 assay, detection of apoptosis, proliferation inhibition-mitotic index. The tested compounds showed higher antineoplastic potential and lower toxicity than the reference compound ellipticine. The results indicate that the new olivacine derivatives are good candidates for future anticancer drugs.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Elipticinas/farmacologia , Apoptose/efeitos dos fármacos , Aspidosperma/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos
9.
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
10.
J Org Chem ; 84(24): 15990-15996, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31746202

RESUMO

A concise formal synthesis of (±)-aspidospermidine via Stork's intermediate, which could be used as a divergent synthesis of Aspidosperma alkaloids, was achieved by employing a ring-opening cyclization of spirocyclopropane with amine followed by a regioselective intramolecular/intermolecular alkylation sequence. Stork's intermediate was synthesized in only six steps from a simple starting material, 1,3-cyclohexanedione, and was converted into (±)-aspidospermidine. To the best of our knowledge, this synthesis of Stork's intermediate involves the least number of steps to date. Furthermore, no protecting groups were used during this synthesis.


Assuntos
Aminas/química , Aspidosperma/química , Alcaloides Indólicos/síntese química , Quinolinas/síntese química , Alquilação , Ciclização , Alcaloides Indólicos/química , Estrutura Molecular , Quinolinas/química , Estereoisomerismo
11.
J Org Chem ; 84(22): 14994-15000, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31646864

RESUMO

The first asymmetric total synthesis of aspidosperma alkaloid (+)-winchinine B was achieved in 12 steps from commercially available materials. A new synthetic strategy which features an efficient aza-Michael addition, a ruthenium-catalyzed transfer dehydrogenation, and an intramolecular palladium-catalyzed oxidative coupling was adopted to install the ABC tricycle system. A one-pot process involving carbonyl reduction/iminium formation/intramolecular conjugate addition developed by our group was utilized to construct the D ring moiety.


Assuntos
Alcaloides/síntese química , Alcaloides/química , Aspidosperma/química , Catálise , Conformação Molecular , Paládio/química , Estereoisomerismo
12.
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
13.
Molecules ; 24(7)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30935100

RESUMO

Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis, a species in this family, contains various monoterpenoid indole alkaloids. In the current study, fourteen known aspidosperma-type monoterpenoid indole alkaloids (1⁻14) were isolated and identified from a methanol extract of the twigs and leaves of B. mekongensis for the first time. Among them, compounds 3, 6, 9, and 13 exhibited similar antiproliferative activity spectra against A549, KB, and multidrug-resistant (MDR) KB subline KB-VIN cells with IC50 values ranging from 0.5⁻0.9 µM. The above alkaloids efficiently induced cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization as well as mitotic bipolar spindle formation. Computer modeling studies indicated that compound 7 likely forms a hydrogen bond (H-bond) with α- or ß-tubulin at the colchicine site. Evaluation of the antiproliferative effects and SAR analysis suggested that a 14,15-double bond or 3α-acetonyl group is critical for enhanced antiproliferative activity. Mechanism of action studies demonstrated for the first time that compounds 3, 4, 6, 7, and 13 efficiently induce cell cycle arrest at G2/M by inhibiting tubulin polymerization by binding to the colchicine site.


Assuntos
Aspidosperma/química , Multimerização Proteica/efeitos dos fármacos , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo
14.
Chemistry ; 25(38): 8916-8935, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30994212

RESUMO

Monoterpenoid indole alkaloids are the major class of tryptamine-derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic organic chemists. In this Review, the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles are discussed.


Assuntos
Alcaloides/síntese química , Aspidosperma/química , Técnicas de Química Sintética/métodos , Strychnos/química , Alcaloides/química , Reação de Cicloadição/métodos , Alcaloides de Triptamina e Secologanina/síntese química , Alcaloides de Triptamina e Secologanina/química
16.
J Nat Prod ; 82(4): 850-858, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30869890

RESUMO

Examination of the EtOH extract of the leaves of the Malayan Tabernaemontana corymbosa resulted in the isolation of four new (1-4) and two known bisindole alkaloids (5, 6) of the Aspidosperma- Aspidosperma type. The structures of these alkaloids were determined based on analysis of the spectroscopic data (NMR and HRESIMS). X-ray diffraction analyses of the related bisindole alkaloids conophylline (5) and conophyllinine (6) established the absolute configurations. Treatment of the bisindole alkaloid conophylline (5) with benzeneselenic anhydride gave, in addition to the known bisindole polyervinine (7) previously isolated from another Malayan Tabernaemontana, another bisindole product, 8, an isolable tautomer of 7. X-ray diffraction analyses yielded the absolute configurations of both bisindoles and in addition showed that polyervinine (7) exists primarily as the neutral dione structure. The bisindoles (1-8) and the related conophylline-type bisindoles (9-13) showed pronounced in vitro growth inhibitory activity against an array of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, A549, HT-29, and HCT 116 cells, with IC50 values for the active compounds in the 0.01-5 µM range.


Assuntos
Aspidosperma/química , Proliferação de Células/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Tabernaemontana/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Estrutura Molecular , Análise Espectral/métodos
17.
J Ethnopharmacol ; 228: 99-109, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30201230

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Aspidosperma excelsum Benth. (Apocynaceae), a native tree in the Brazilian Amazonia, is traditionally used to treat various diseases, including malaria. AIM OF STUDY: To investigate the chemical constitution, antiplasmodial activity and cytotoxicity of samples obtained from A. excelsum trunk bark by different procedures aiming to evaluate their potential as an antimalarial phytomedicine. MATERIALS AND METHODS: A hydroethanolic extract and alkaloid extracts were prepared and assayed for antiplasmodial activity and cytotoxicity against chloroquine-resistant Plasmodium falciparum (W2 strain) and HepG2 cells, respectively. Taking into account the known occurrence and antimalarial activity of Aspidosperma monoterpene indole alkaloids (MIA), acid-base extractions were carried out and the fractions were assayed for antiplasmodial activity and cytotoxicity. All the samples were analysed by hyphenated chromatographic techniques, such as UPLC-DAD-ESI-MS/MS and HRMS (HPLC-MS MicroTOF), comparing their chemical composition to the literature data. RESULTS: The hydroethanolic extract disclosed a moderate in vitro activity against chloroquine-resistant Plasmodium falciparum (W2 strain) with IC50 23.68 ± 3.08 µg/mL), low cytotoxicity to HepG2 cells (> 250 µg/mL) and good SI (> 10.56). A total of 20 known monoterpene indole alkaloids were identified, seven of which are here firstly described for A. excelsum. Known highly active alkaloids, namely demethylaspidospermine, aspidocarpine, and ochrolifuanine are present in active alkaloid fractions and might contribute to their observed antiplasmodial effect. An alkaloid fraction (Ae-Alk2), obtained directly from trunk bark by extraction with dil. aqueous HCl, pointed out for its activity (IC50 8.75±2.26 µg/mL, CC50 185.14±1.97 µg/mL, SI 21.16) and should be highlighted as the most promising out of the assayed samples. CONCLUSION: The present results represent a preliminary support to the alleged antimalarial use of A. excelsum trunk bark and allowed to highlight alkaloid fractions as promising phytomedicines.


Assuntos
Antimaláricos/farmacologia , Aspidosperma , Alcaloides Indólicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/análise , Brasil , Cloroquina , Cromatografia Líquida , Resistência Microbiana a Medicamentos , Eritrócitos/microbiologia , Células Hep G2 , Humanos , Alcaloides Indólicos/análise , Medicina Tradicional , Casca de Planta , Espectrometria de Massas em Tandem
18.
J Ethnopharmacol ; 231: 125-140, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30395977

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Species of Aspidosperma are known popularly as "peroba, guatambu, carapanaúba, pau-pereiro" and "quina". The genus can be found in the Americas, mainly between Mexico and Argentina. Many species of Aspidosperma are used by the population in treating cardiovascular diseases, malaria, fever, diabetes and rheumatism. The phytochemical aspects of the species of the genus Aspidosperma have been studied extensively. The monoterpene indole alkaloids are the main secondary metabolites in Aspidosperma species, and about 250 of them have been isolated showing a considerable structural diversity. Several of them have showed some important pharmacological activities. Aspidosperma subincanum Mart. and Aspidosperma tomentosum Mart. (Apocynaceae) are Brazilian species widely used by the population to treat diabetes mellitus, hypercholesterolemia. The pharmacological activities of both species have been investigated and the biological properties described can be related to their isolated indole alkaloids. However, more pharmacological studies are needed in order to justify the use of these species in folk medicine. In this review, we present reports mainly focused on chemical and biological studies and their relationship with the ethnopharmacological use of both Aspidosperma species. AIM OF THE STUDY: The aim of this review is to present their ethnopharmacological use as correlated to their biological activities as described for the extracts and isolated compounds from Aspidosperma subincanum Mart. and Aspidosperma tomentosum Mart. In addition, some aspects related to the biosynthetic pathways are discussed, also NMR assignments and some synthesis information about indole alkaloids from both Aspidosperma species are included. MATERIAL AND METHODS: The bibliographic search was made in theses and dissertations using some databases such as NDLTD (Networked Digital Library of Theses and Dissertations), OATD (Open Access Theses and Dissertations) and Google Scholar. More data were gathered from books, Brazilian journals and articles available on electronic databases such as, Google Scholar, PubChem, Scifinder, Web of Science, SciELO, PubMed and Science Direct. Additionally, the Google Patents and Espacenet Patent Search (EPO) were also consulted. The keywords Aspidosperma, A. subincanum, A. tomentosum, indole alkaloids were used in the research. The languages were restricted to Portuguese, English and Spanish and references were selected according to their relevance. RESULTS: A. subincanum Mart. and A. tomentosum Mart. (Apocynaceae) are Brazilian species widely used by the population to treat a few diseases. Extracts and isolated compounds of both species have shown antitumor and antimalarial activities. The antitumor activity of isolated compounds has been extensively studied. However, the antiplasmodial activity needs to be investigated further as well as the anti-inflammatory, anti-hyperlipidemic and anorexigenic activities. From A. subincanum twenty-one indole alkaloids were isolated and some of them have been extensively studied. From the leaves and bark of A. tomentosum four alkaloids and one flavonoid were isolated. Furthermore, CG-MS analysis of seeds, branches, leaves and arils identified nine indole alkaloids. Stemmadenine has been proposed as a precursor of indole alkaloids obtained from some species of Aspidosperma. Many of the biosynthetic steps have been characterized at the enzymatic level and appropriate genes have been identified, however, other steps have yet to be investigated and they are still controversial. Some isolated alkaloids from A. subincanum and A. tomentosum were identified only by mass spectrometry. In many cases, their NMR data was either not available or was incomplete. The described meta-analysis of the available NMR data revealed that the chemical shifts belonging to the indole ring might be used to characterize this class of alkaloids within complex matrices such as plant extracts. The biological activities and the structural complexity of these compounds have stimulated the interest of many groups into their synthesis. In this review, some information about the synthesis of indole alkaloids and their derivatives was presented. CONCLUSIONS: A. subincanum and A. tomentosum are used by the population of Brazil to treat many diseases. A few biological activities described for the extracts and isolated compounds of both species are in agreement with the ethnopharmacological use for others species of Aspidosperma, such as, antimalarial, the treatment of diabetes and other illnesses. These species are sources of leading compounds which can be used for developing new drugs. In addition, other biological activities reported and suggested by ethnopharmacological data have yet to be investigated and could be an interesting area in the search for new bioactive compounds.


Assuntos
Aspidosperma , Fitoterapia , Alcaloides/química , Alcaloides/metabolismo , Alcaloides/farmacologia , Animais , Aspidosperma/química , Aspidosperma/metabolismo , Brasil , Etnobotânica , Humanos , Medicina Tradicional , Compostos Fitoquímicos/química , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia
19.
Org Biomol Chem ; 16(48): 9409-9419, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30500039

RESUMO

Aspidospermidine, vincadifformine, 1,2-dehydroaspidospermidine, goniomitine, and quebrachamine, five Aspidosperma alkaloids distributed within three structurally diverse topologies, were synthesized from a single molecular scaffold, namely indole-valerolactam 6. This common intermediate can be divergently manipulated, through the incorporation of conformational and electronic constraints that influence the chemo-selectivity of the iminium ion derived therefrom, between three different reaction paths: N(1) vs. C(3) cyclization (indole numbering) vs. over-reduction. Moreover, a catalytic carbene insertion for direct C(3)-H indole functionalization is reported for the first time in an approach to goniomitine (4), and a following tandem ester reduction/iminium generation/cyclization secured its tetracyclic system. The development of a highly diastereoselective one-pot hemi-reduction/cyclization/deprotection process to obtain a cis-pyridocarbazole directly allowed the synthesis of pentacyclic Aspidosperma alkaloids 1, 2, and 3.


Assuntos
Alcaloides/síntese química , Aspidosperma/química , Alcaloides Indólicos/síntese química , Quinolinas/síntese química , Alcaloides/química , Técnicas de Química Sintética , Ciclização , Alcaloides Indólicos/química , Quinolinas/química , Estereoisomerismo
20.
Malar J ; 17(1): 436, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30477525

RESUMO

BACKGROUND: Several species of Aspidosperma plants are referred to as remedies for the treatment of malaria, especially Aspidosperma nitidum. Aspidosperma pyrifolium, also a medicinal plant, is used as a natural anti-inflammatory. Its fractionated extracts were assayed in vitro for activity against malaria parasites and for cytotoxicity. METHODS: Aspidosperma pyrifolium activity was evaluated against Plasmodium falciparum using extracts in vitro. Toxicity towards human hepatoma cells, monkey kidney cells or human monocytes freshly isolated from peripheral blood was also assessed. Anti-malarial activity of selected extracts and fractions that presented in vitro activity were tested in mice with a Plasmodium berghei blood-induced infection. RESULTS: The crude stem bark extract and the alkaloid-rich and ethyl acetate fractions from stem extract showed in vitro activity. None of the crude extracts or fractions was cytotoxic to normal monkey kidney and to a human hepatoma cell lines, or human peripheral blood mononuclear cells; the MDL50 values of all the crude bark extracts and fractions were similar or better when tested on normal cells, with the exception of organic and alkaloidic-rich fractions from stem extract. Two extracts and two fractions tested in vivo caused a significant reduction of P. berghei parasitaemia in experimentally infected mice. CONCLUSION: Considering the high therapeutic index of the alkaloidic-rich fraction from stem extract of A. pyrifolium, it makes the species a candidate for further investigation aiming to produce a new anti-malarial, especially considering that the active extract has no toxicity, i.e., no mutagenic effects in the genototoxicity assays, and that it has an in vivo anti-malarial effect. In its UPLC-HRMS analysis this fraction was shown to have two major components compatible with the bisindole alkaloid Leucoridine B, and a novel compound, which is likely to be responsible for the activity against malaria parasites demonstrated in in vitro tests.


Assuntos
Antimaláricos/farmacologia , Aspidosperma/química , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/administração & dosagem , Antimaláricos/isolamento & purificação , Antimaláricos/toxicidade , Brasil , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Haplorrinos , Humanos , Malária/terapia , Camundongos , Carga Parasitária , Parasitemia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Plasmodium berghei/isolamento & purificação , Resultado do Tratamento
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