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1.
Chem Pharm Bull (Tokyo) ; 68(2): 103-116, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009077

RESUMO

The merits of biogenetic considerations in the chemical syntheses of natural products have been emphasized by describing the total syntheses of Lycopodium alkaloids; lycodine, flabellidine, lycopodine, and flabelliformine, as well as monoterpenoid indole alkaloids; C-mavacurine, kopsiyunnanine K, koumine, and 11-methoxy-19R-hydroxygelselegine.


Assuntos
Alcaloides/síntese química , Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Lycopodium/química , Alcaloides de Triptamina e Secologanina/síntese química , Alcaloides/química , Produtos Biológicos/química , Alcaloides de Triptamina e Secologanina/química
2.
Top Curr Chem (Cham) ; 378(2): 22, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32030596

RESUMO

Heterocyclic compounds having a nitrogen atom in the ring exhibit very interesting biological activities. Indole is the core structure of many bioactive compounds owing to its high affinity to bind with most biological targets. Indole is an electron-rich compound and generally prefers electrophilic rather than nucleophilic substitution. Hence, many important indole derivatives are difficult to synthesize through the conventional reactivity of indole. This limitation can be avoided by using the umpolung, from the German word meaning polarity inversion. In umpolung, the indole molecule, especially the C2 and C3 positions, behave as an electrophile. As C2-functionalized indoles have substantial importance in synthetic and pharmaceutical chemistry, this review focuses on the C2 umpolung of indoles via the indirect approach which is less explored. Unlike direct approaches of indole umpolung, indirect methods have several advantages and therefore a number of research articles have been published in this field. But no review is available up till now. This is the first review on this topic and we believe that it will surely motivate the readers to work in this area further.


Assuntos
Carbono/química , Indóis/química , Alcaloides/síntese química , Alcaloides/química , Catálise , Ciclização , Iodo/química , Quinolinas/síntese química , Quinolinas/química , Ácidos Sulfínicos/química
3.
Alkaloids Chem Biol ; 83: 1-112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32098648

RESUMO

Lamellarins are marine alkaloids containing fused 14-phenyl-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinoline or non-fused 3,4-diarylpyrrole-2-carboxylate ring systems. To date, more than 50 lamellarins have been isolated from a variety of marine organisms, such as mollusks, tunicates, and sponges. Many of them, especially fused type I lamellarins, exhibit impressive biological activity, such as potent cytotoxicity, topoisomerase I inhibition, protein kinases inhibition, and anti-HIV-1 activity. Due to their useful biological activity and limited availability from natural sources, a number of synthetic methods have been developed. In this chapter, we present an updated and comprehensive review on lamellarin alkaloids summarizing their isolation, synthesis, and biological activity.


Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/isolamento & purificação , Pirróis/farmacologia , Inibidores da Topoisomerase I/farmacologia , Alcaloides/síntese química , Alcaloides/química , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Pirróis/síntese química , Pirróis/química , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/isolamento & purificação
4.
Eur J Med Chem ; 186: 111854, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31753515

RESUMO

Small Conductance Calcium (Ca2+)-activated potassium (K+) channels (SKCa) are now proved to be involved in many cancer cell behaviors such as proliferation or migration. The SK3 channel isoform was particularly described in breast cancer where it can be associated with the Orai1 Ca2+ channel to form a complex that regulates the Ca2+ homeostasis during tumor development and acts as a potent mediator of bone metastases development in vivo. Until now, very few specific blockers of Orai1 and/or SK3 have been developed as potential anti-metastatic compounds. In this study, we illustrated the synthesis of new families of lipophilic pyridine and tetrahydropyridine derivatives designed as potential modulators of SK3 channel. The toxicity of the newly synthesized compounds and their migration effects were evaluated on the breast cancer cell line MDA-MB-435s. Two molecules (7a and 10c) demonstrated a significant decrease in the SK3 channel-dependent migration as well as the SK3/Orai1-related Ca2+ entry. Current measurements showed that these compounds are more likely SK3-selective. Taken all together these results suggest that such molecules could be considered as promising anti-metastatic drugs in breast cancer.


Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Lipídeos/farmacologia , Pirrolidinas/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Alcaloides/síntese química , Alcaloides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Lipídeos/química , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 185: 111770, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711793

RESUMO

Piperine has been associated with neuroprotective effects and monoamine oxidase (MAO) inhibition, thus being an attractive scaffold to develop new antiparkinsonian agents. Accordingly, we prepared a small library of piperine derivatives and screened the inhibitory activities towards human MAO isoforms (hMAO-A and hMAO-B). Structure-activity relationship (SAR) studies pointed out that the combination of α-cyano and benzyl ester groups increased both potency and selectivity towards hMAO-B. Kinetic experiments with compounds 7, 10 and 15 indicated a competitive hMAO-B inhibition mechanism. Compounds 15 and 16, at 10 µM, caused a small but significant decrease in P-gp efflux activity in Caco-2 cells. Compound 15 stands out as the most potent piperine-based hMAO-B inhibitor (IC50 = 47.4 nM), displaying favourable drug-like properties and a broad safety window. Compound 15 is thus a suitable candidate for lead optimization and the development of multitarget-directed ligands.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Benzodioxóis/síntese química , Benzodioxóis/química , Células CACO-2 , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/química , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
Mini Rev Med Chem ; 19(19): 1577-1598, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31538893

RESUMO

Alzheimer, a progressive disease, is a common term for memory loss which interferes with daily life through severe influence on cognitive abilities. Based on the cholinergic hypothesis, and Xray crystallographic determination of the structure of acetylcholinesterase (AChE) enzyme, the level of acetylcholine (ACh, an important neurotransmitter associated with memory) in the hippocampus and cortex area of the brain has a direct effect on Alzheimer. This fact encourages scientists to design and synthesize a wide range of acetylcholinesterase inhibitors (AChEIs) to control the level of ACh in the brain, keeping in view the crystallographic structure of AChE enzyme and drugs approved by the Food and Drug Administration (FDA). AChEIs have slightly diverse pharmacological properties, but all of them work by inhibiting the segregation of ACh by blocking AChE. We reviewed significant scaffolds introduced as AChEIs. In some studies, the activity against butyrylcholinesterase (BuChE) has been evaluated as well because BuChE is a similar enzyme to neuronal acetylcholinesterase and is capable of hydrolyzing ACh. In order to study AChEIs effectively, we divided them structurally into 12 classes and briefly explained effective AChEIs and compared their activities against AChE enzyme.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Desenho de Fármacos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Alcaloides/síntese química , Alcaloides/química , Doença de Alzheimer/patologia , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/uso terapêutico , Donepezila/síntese química , Donepezila/química , Humanos , Rivastigmina/síntese química , Rivastigmina/química , Tacrina/síntese química , Tacrina/química
7.
Artigo em Inglês | MEDLINE | ID: mdl-31279971

RESUMO

New psychoactive substances have been introduced into the market in the last years due to their unregulated status. Synthetic cathinones are one of their main representatives, and they have shown to produce neonatal complications. It is important to have objective tools to identify in utero exposure to drugs that have shown to produce neonatal complications. An analytical method was developed and fully validated for the determination of common synthetic cathinones, including methylone, methedrone, mephedrone, 3,4-methylenedioxypyrovalerone (MDPV), (±)-4-fluoromethamphetamine and 4-fluoromethcathinone in meconium. Meconium (0.25 ±â€¯0.02 g) was homogenized with methanol by sonication for 30 min. After centrifugation, the sample was extracted with Oasis MCX columns. The analysis was performed by LC-MS/MS using an Atlantis T3 column (3 µm, 2.1 × 50 mm) and a gradient with acetonitrile and 0.1% formic acid in water. Method validation included the following parameters: selectivity (no endogenous or exogenous interferences), limits of detection (n = 3, 0.5-1 ng/g) and quantification (n = 3, 1-2 ng/g), linearity (n = 5, LOQ-200 ng/g), imprecision (n = 15, 0% to 10%), accuracy (n = 15, 87.3% to 97.8%), matrix effect (n = 10, -76% to -28.1%), extraction efficiency (n = 6, 63.7% to 91.3%), total process efficiency (n = 6, 16% to 60.2%) and stability for 72 h in the autosampler (n = 3, %loss = -6.7% to 5.1%). The method was applied to 28 meconium specimens.


Assuntos
Alcaloides/análise , Cromatografia Líquida de Alta Pressão/métodos , Mecônio/química , Espectrometria de Massas em Tandem/métodos , Adulto , Alcaloides/síntese química , Feminino , Humanos , Gravidez , Transtornos Relacionados ao Uso de Substâncias/diagnóstico
8.
Mar Drugs ; 17(5)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137661

RESUMO

Pinnatoxins (PnTXs) A-H constitute an emerging family belonging to the cyclic imine group of phycotoxins. Interest has been focused on these fast-acting and highly-potent toxins because they are widely found in contaminated shellfish. Despite their highly complex molecular structure, PnTXs have been chemically synthetized and demonstrated to act on various nicotinic acetylcholine receptor (nAChR) subtypes. In the present work, PnTX-A, PnTX-G and analogue, obtained by chemical synthesis with a high degree of purity (>98%), have been studied in vivo and in vitro on adult mouse and isolated nerve-muscle preparations expressing the mature muscle-type (α1)2ß1δε nAChR. The results show that PnTX-A and G acted on the neuromuscular system of anesthetized mice and blocked the compound muscle action potential (CMAP) in a dose- and time-dependent manner, using a minimally invasive electrophysiological method. The CMAP block produced by both toxins in vivo was reversible within 6-8 h. PnTX-A and G, applied to isolated extensor digitorum longus nerve-muscle preparations, blocked reversibly isometric twitches evoked by nerve stimulation. The action of PnTX-A was reversed by 3,4-diaminopyridine. Both toxins exerted no direct action on muscle fibers, as revealed by direct muscle stimulation. PnTX-A and G blocked synaptic transmission at mouse neuromuscular junctions and PnTX-A amino ketone analogue (containing an open form of the imine ring) had no effect on neuromuscular transmission. These results indicate the importance of the cyclic imine for interacting with the adult mammalian muscle-type nAChR. Modeling and docking studies revealed molecular determinants responsible for the interaction of PnTXs with the muscle-type nAChR.


Assuntos
Alcaloides/farmacologia , Músculo Esquelético/efeitos dos fármacos , Compostos de Espiro/farmacologia , Esteróis/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Alcaloides/síntese química , Animais , Feminino , Masculino , Camundongos , Bloqueadores Neuromusculares/síntese química , Bloqueadores Neuromusculares/farmacologia , Antagonistas Nicotínicos/síntese química , Antagonistas Nicotínicos/farmacologia , Ligação Proteica/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Compostos de Espiro/síntese química , Esteróis/síntese química
9.
Eur J Med Chem ; 176: 149-161, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103896

RESUMO

Plants are vital for the wellbeing of humankind in a variety of ways. Some plant extracts contain antimicrobial properties that can treat different pathogens. Most of the world's population relies on medicinal plants and natural products for their primary health care needs. Therefore, there is a growing interest in natural products, medicinal plants, and traditional medicine along with a desire to design and develop novel plant-based pharmaceuticals. These plant-based pharmaceuticals may address the concerns of reduced efficacy of synthetic antibiotics due to the emergence of drug-resistant pathogens. In this regard, some plant extracts from black pepper (Piper nigrum) with antimicrobial properties, including piperine, have the potential to be used as natural dietary supplements together with modern therapeutic approaches. This review highlights possible applications of piperine as the active compound in the fields of rational drug design and discovery, pharmaceutical chemistry, and biomedicine. We discuss different extraction methods and pharmacological effects of the analyzed substance to pave the way for further research strategies and perspectives towards the development of novel herbal products for better healthcare solutions.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Piper nigrum/química , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/análise , Alcaloides/síntese química , Alcaloides/isolamento & purificação , Animais , Benzodioxóis/análise , Benzodioxóis/síntese química , Benzodioxóis/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Piperidinas/análise , Piperidinas/síntese química , Piperidinas/isolamento & purificação , Alcamidas Poli-Insaturadas/análise , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/isolamento & purificação
10.
Eur J Med Chem ; 173: 76-89, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30986573

RESUMO

A series of (±)-trans-dihydronarciclasine and (±)-trans-dihydrolycoricidine derivatives with variously substituted ring A was synthesised and evaluated for their antiproliferative activity against 60 human tumour cell lines (NCI60), representing leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate, as well as kidney in vitro. Among the 13 alkaloids screened, (±)-trans-dihydronarciclasine showed the highest potency as a cytotoxic molecule. A structure-activity relationship (SAR) study indicated that the presence of a hydroxy group at position 7 and a rigid, 1,3-benzodioxole scaffold were essential for the antiproliferative activity.


Assuntos
Alcaloides/farmacologia , Alcaloides de Amaryllidaceae/farmacologia , Antineoplásicos/farmacologia , Alcaloides/síntese química , Alcaloides/química , Alcaloides de Amaryllidaceae/síntese química , Alcaloides de Amaryllidaceae/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
11.
Molecules ; 24(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987238

RESUMO

The behavior of 2-naphthol and 7-bromo-2-naphthol as organic photoacids are exploited in organic synthesis for the preparation of benzyl sulfides (using a trichloroacetimidate derivative as the starting substrate) and polycyclic amines via acid catalyzed condensation of 1,2,3,4-tetrahydroisoquinoline with aldehydes.


Assuntos
Ácidos/química , Prótons , Alcaloides/síntese química , Alcaloides/química , Compostos de Benzil/síntese química , Compostos de Benzil/química , Catálise
12.
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
13.
Org Lett ; 21(9): 3193-3197, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30995050

RESUMO

An asymmetric synthesis of C14-desmethylene corialactone D is described on the basis of strategic application of a metallacycle-mediated annulative cross-coupling reaction, a Still [2,3]-Wittig rearrangement, and Morken's hydroxyl-directed diboration reaction. While representing a convenient approach to access novel compositions of matter inspired by the sesquiterpenoid natural product class (including classic natural product synthesis targets including the picrotaxanes and dendrobine), these studies have led to the discovery of natural product-inspired agents that inhibit nerve growth factor (NGF)-mediated neurite outgrowth in PC-12 cells.


Assuntos
Alcaloides/síntese química , Lactonas/síntese química , Fator de Crescimento Neural/antagonistas & inibidores , Crescimento Neuronal/efeitos dos fármacos , Sesquiterpenos/síntese química , Alcaloides/farmacologia , Animais , Lactonas/farmacologia , Células PC12 , Ratos , Sesquiterpenos/farmacologia , Relação Estrutura-Atividade
14.
Molecules ; 24(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897818

RESUMO

A total of 18 matrine derivatives were designed, synthesized, and evaluated for their inhibitory effect against TGF-ß1-induced total collagen accumulation in human fetal lung fibroblast MRC-5 cell lines. Among them, compound 3f displayed the most potent anti-fibrotic activity (IC50 = 3.3 ± 0.3 µM) which was 266-fold more potent than matrine. 3f significantly inhibited the fibroblast-to-myofibroblast transition and extracellular matrix production of MRC-5 cells. The TGF-ß/small mothers against decapentaplegic homologs (Smad) signaling was also inhibited by 3f, as evidenced by inhibition of cytoplasm-to-nuclear translocation of Smad2/3 and suppression of TGF-ß1-induced upregulation of TGF-ß receptor type I (TGFßRI). Additionally, 3f exhibited potent inhibitory effects against TGF-ß1-induced fibroblasts migration. These data suggested that 3f might be a potential agent for the treatment of idiopathic pulmonary fibrosis via repression of the TGFß/Smad signaling pathway.


Assuntos
Alcaloides/química , Alcaloides/síntese química , Quinolizinas/química , Quinolizinas/síntese química , Alcaloides/farmacologia , Linhagem Celular , Colágeno/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Imuno-Histoquímica , Indóis/química , Espectroscopia de Ressonância Magnética , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Quinolizinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Crescimento Transformador beta1/farmacologia
15.
Molecules ; 24(6)2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30889939

RESUMO

The enantioselective synthesis (3.7% overall yield in nine steps from 2) and biological screening of the ethyl analog of the macrocyclic marine alkaloid haliclorensin C (compound 5) are reported. Amino alcohol 3, generated by a LiNH2BH3-promoted reductive ring-opening/debenzylation sequence from phenylglycinol-derived lactam 2, was used as the starting chiral linear building block. Incorporation of the undecene chain via the nosyl derivative 12, methylenation of the pentanol moiety, and a ring-closing metathesis are the key steps of the synthesis.


Assuntos
Alcaloides/química , Alcaloides/síntese química , Organismos Aquáticos/química , Cloreto de Etil/química , Estereoisomerismo
16.
Molecules ; 24(4)2019 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-30781470

RESUMO

Following two orthogonal synthetic routes, a series of all four possible A-ring amino derivatives of the natural product Luotonin A (a known Topoisomerase I inhibitor) was synthesized. In both strategies, intramolecular cycloaddition reactions are the key step. The target compounds were obtained in good yields by mild catalytic transfer hydrogenation of the corresponding nitro precursors. In-vitro evaluation of the antiproliferative activity towards human tumor cell lines revealed the 4-amino compound (5b) to be the most effective agent, showing an interesting profile of cytotoxic activity. Among other effects, a significant G2/M cell cycle arrest was observed for this compound, suggesting that either Topoisomerase I is not the only biological target, or that some atypical mechanism is responsible for inhibition of this enzyme.


Assuntos
Alcaloides/síntese química , Alcaloides/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Quinonas/síntese química , Quinonas/farmacologia , Alcaloides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirróis/química , Quinonas/química , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia
17.
Molecules ; 24(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717179

RESUMO

New quinazolinone derivatives of the marine-derived alkaloids fiscalin B (3) and fumiquinazoline G (1), with neuroprotective and antitumor effects, were synthesized. Eleven quinazolinone-containing indole alkaloids were synthesized, proceeding the anti analogs via a one-pot method, and the syn analogs by the Mazurkiewicz-Ganesan approach. The neuroprotection capacity of these compounds on the rotenone-damage human neuroblastoma cell SH-SY5y was evaluated using the MTT assay. Compounds 1, 3, 5, and 7 showed more than 25% protection. The antitumor activity was investigated using the sulforhodamine B assay and some compounds were tested on the non-malignant MCF-12A cells. Fumiquinazoline G (1) was the most potent compound, with GI50 values lower than 20 µM. Compounds 5, 7, and 11 were more active in all tumor cell lines when compared to their enantiomers. Compounds 5, 7, 10, and 11 had very little effect in the viability of the non-malignant cells. Differences between enantiomeric pairs were also noted as being essential for these activities the S-configuration at C-4. These results reinforce the previously described activities of the fiscalin B (3) as substance P inhibitor and fumiquinazoline G (1) as antitumor agent showing potential as lead compounds for the development of drugs for treatment of neurodegenerative disorders and cancer, respectively.


Assuntos
Alcaloides/síntese química , Antineoplásicos/síntese química , Fármacos Neuroprotetores/síntese química , Peptidomiméticos/síntese química , Quinazolinonas/síntese química , Alcaloides/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Peptidomiméticos/farmacologia , Quinazolinonas/farmacologia , Relação Estrutura-Atividade
18.
Bioorg Med Chem ; 27(5): 832-840, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711309

RESUMO

Cryptococcus neoformans is the leading cause of cryptococcal meningitis, which is associated with high mortality due to lack of effective treatment. Herein a series of tricyclic isoxazole derivatives with excellent anti-cryptococcal activities were identified by structural simplification and scaffold hopping of antifungal natural product sampangine. Particularly, compound 8a showed promising features as an anti-cryptococcal lead compound. It was highly active against C. neoformans (MIC80 = 0.031 µg/mL), which was more potent than fluconazole and voriconazole. Moreover, compound 8a showed potent fungicidal activity and had potent inhibitory effects against important virulence factors (i.e. biofilm, melanin and urease) of C. neoformans. Preliminary antifungal mechanism investigation revealed that compound 8a induced apoptosis of C. neoformans cells and arrested the cell cycle at the G1/S phase.


Assuntos
Alcaloides/farmacologia , Antifúngicos/farmacologia , Cryptococcus neoformans/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Isoxazóis/farmacologia , Naftiridinas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Antifúngicos/síntese química , Antifúngicos/química , Apoptose/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Descoberta de Drogas , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Isoxazóis/síntese química , Isoxazóis/química , Melaninas/antagonistas & inibidores , Testes de Sensibilidade Microbiana , Estrutura Molecular , Naftiridinas/síntese química , Naftiridinas/química , Relação Estrutura-Atividade , Urease/antagonistas & inibidores
19.
J Antibiot (Tokyo) ; 72(6): 494-497, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30792516

RESUMO

A transannular reaction was proposed to access the Lycopodium alkaloid lycopodine. A key bicyclic precursor was synthesized via a ring-closing metathesis reaction. Initial evaluations of the transannular aza-Prins reaction to synthesize lycopodine were reported and discussed.


Assuntos
Alcaloides/síntese química , Quinolizinas/síntese química , Alcaloides/química , Lycopodium/química , Modelos Moleculares , Estrutura Molecular , Quinolizinas/química
20.
J Immunol ; 202(5): 1350-1362, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30674573

RESUMO

MYMD-1 is a synthetic derivative of tobacco alkaloids, compounds that possess immunoregulatory properties and have been linked to the epidemiological observation that smoking reduces the odds of developing thyroid Abs and hypothyroidism. To assess the effect and mechanism(s) of the action of MYMD-1, we chose the NOD.H-2h4 mouse model of spontaneous thyroiditis. We began in vitro using T cells isolated from NOD.H-2h4 spleens and found that MYMD-1 suppressed TNF-α production by CD4+ T cells in a dose-dependent manner. We then treated 58 NOD.H-2h4 mice for 12 wk with either unsupplemented water that contained (10 mice) or did not contain (16 mice) MYMD-1 (185 mg/l) or water supplemented with sodium iodide (500 mg/l) that contained (16 mice) or did not contain (16 mice) MYMD-1. Mice were bled at baseline and then every 2 wk until sacrifice. MYMD-1 decreased the incidence and severity (p < 0.001) of thyroiditis, as assessed by histopathology. Similarly, the number of CD3+ T cells and CD19+ B cells infiltrating the thyroid was dampened by MYMD-1, as assessed by flow cytometry. Interestingly, the subset of thyroidal CD3+CD4+Tbet+RORγT- effector Th1 cells and the systemic levels of TNF-α were decreased by MYMD-1. Serum thyroglobulin Abs decreased in the MYMD-1 group. Thyroid hormones did not differ among the four groups, whereas thyroid-stimulating hormone increased upon iodine supplementation but remained normal in MYMD-1-treated mice. Overall, the study suggests that MYMD-1 ameliorates thyroiditis acting on specific lymphoid subsets. Further studies, including other models of autoimmunity, will confirm the potential clinical use of MYMD-1 as a novel immunometabolic regulator.


Assuntos
Alcaloides/farmacologia , Mediadores da Inflamação/farmacologia , Tireoidite Autoimune/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Alcaloides/síntese química , Alcaloides/química , Animais , Feminino , Mediadores da Inflamação/síntese química , Mediadores da Inflamação/química , Masculino , Camundongos , Camundongos Endogâmicos NOD , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Tireoidite Autoimune/imunologia , Tabaco/química , Fator de Necrose Tumoral alfa/imunologia
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