RESUMO
As an extended study on development of anti-Alzheimer's disease agent, we newly synthesized various dihydrofuran-fused perhydrophenanthrenes via o-quinodimethane chemistry. This study revealed that the introduction of carbon side-chain on 8-position or removal of the acetal moiety on 3-position arose a cytotoxicity on rat cortical neurons. On the other hand, the ethereal or thio-ethereal substituent on 8-position enhanced the elongation effect on Aß-damaged neurons. The necessity of the cyano group on 10b position was also proved in this structure-activity-relationship study.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Furanos/química , Furanos/farmacologia , Fenantrenos/química , Fenantrenos/farmacologia , Animais , Modelos Químicos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
As a part of our research program on developing novel anti-Alzheimer's disease medicines, several dihydrofuran-fused perhydrophenanthrenes (DFs) possessing a phenolic hydroxyl group were found to exhibit potent dendritic and axonal regeneration activities. Introduction of a methoxy group into the perhydrophenanthrene skeleton was successfully achieved via a PhI(OAc)(2)-mediated phenolic oxidation of a benzocyclobutene nucleus and subsequent tandem intramolecular electrocyclic reactions based on o-quinodimethane chemistry. We could reveal that a new methoxy derivative having a phenolic hydroxyl group exerted the most significant effects on the dendritic and axonal extensions in the damaged neurons, among DFs examined in this study.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Fenantrenos/química , Fenol/química , Catecóis/química , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Modelos Químicos , Estrutura Molecular , Nêutrons , Oxigênio/química , Fenóis/químicaRESUMO
Brain-derived neurotrophic factor (BDNF) plays a fundamental role in neuronal synaptic plasticity. A decrease of plasticity in the brain may be related to the pathogenesis of neurodegenerative or psychiatric disorders. Pyrethroid insecticides, which affect sodium channels in neurons, are widely used to control insect pests in agriculture and in the home. We previously found that deltamethrin (DM), a type II pyrethroid, increased Bdnf mRNA expression in cultured rat cortical neurons. However, the cyano group at the α-position of type II pyrethroids is likely susceptible to hydrolytic degradation and, its degraded product, hydrogen cyanide, could generate a cellular toxicity in the human body. To determine if the cyano group is required for the Bdnf exon IV-IX (Bdnf eIV-IX) mRNA expression induced by type II pyrethroids, for this study we synthesized a series of derivatives, in which the cyano group at the α-position was replaced with an ethynyl group. Then we added various substituents at the terminal position of the ethynyl group, and biologically evaluated the effects of these derivatives on Bdnf eIV-IX mRNA expression. These ethynyl derivatives induced the Bdnf eIV-IX mRNA expression in a concentration-dependent manner, at varying levels but lower levels than that evoked by DM. The mechanisms for the Bdnf induction and the morphological changes of neurons were the same whether the cyano or ethynyl group was included in the compounds.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Inseticidas/farmacologia , Neurônios/efeitos dos fármacos , Piretrinas/farmacologia , RNA Mensageiro/efeitos dos fármacos , Animais , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Inseticidas/síntese química , Inseticidas/química , Conformação Molecular , Neurônios/citologia , Neurônios/metabolismo , Piretrinas/síntese química , Piretrinas/química , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Canais de Sódio/metabolismo , Relação Estrutura-AtividadeRESUMO
As one of our ongoing research project concerning development of a novel anti-influenza virus agent, dihydrofuran-fused perhydrophenanthrenes were derivatized by means of Williamson ether synthesis and Suzuki-Miyaura cross coupling reactions. Newly synthesized compounds were subjected to evaluation of anti-influenza virus activity using influenza A/Aichi/2/68 (H3N2 subtype) virus strain by a plaque titration method. These investigations revealed that incorporation of benzyl-type ether substituents was effective for exerting the inhibition activity of influenza virus proliferation.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Furanos/química , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Fenantrenos/síntese química , Fenantrenos/farmacologia , Animais , Antivirais/química , Células Cultivadas , Cães , Vírus da Influenza A Subtipo H3N2/crescimento & desenvolvimento , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Fenantrenos/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Nonalcoholic fatty liver disease (NAFLD) is an abnormal liver metabolism often observed with insulin resistance and metabolic syndrome. Calorie restriction is a useful treatment for NAFLD and reportedly prolongs the life spans of several species in which sirtuin plays an important role. In this study, we examined whether the activation of SIRT1, a mammalian ortholog of sirtuin, may ameliorate the development of NAFLD. Monosodium glutamate (MSG) mice, which exhibited obesity and insulin resistance, were treated with SRT1720, a specific SIRT1 activator from the age of 6-16 wk. Sixteen-week-old MSG mice exhibited increased liver triglyceride content and elevated levels of aminotransferase. SRT1720 treatment significantly reduced these levels without affecting body weight or food intake. These results suggested that the administration of SRT1720 ameliorated the development of NAFLD in MSG mice. The expressions of lipogenic genes, such as sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase, and the serum lipid profiles, including free fatty acids, were elevated in MSG mice and were reduced by SRT1720 treatment. SRT1720 treatment also reduced the expressions of lipogenic genes in cultured HepG2 cells. Furthermore, SRT1720 treatment decreased the expressions of marker genes for oxidative stress and inflammatory cytokines in the liver of MSG mice. Taken together, SRT1720 treatment may reduce liver lipid accumulation, at least in part, by directly reducing the expressions of lipogenic genes. The reduction of oxidative stress and inflammation may also be involved in the amelioration of NAFLD.
Assuntos
Fígado Gorduroso/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Sirtuína 1/metabolismo , Glutamato de Sódio , Animais , Biotransformação/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Ingestão de Alimentos/efeitos dos fármacos , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/enzimologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Immunoblotting , Imunoprecipitação , Lipogênese/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Various artificial macrosphelides were designed and synthesized, including ring-enlarged analogues and epothilone-hybrid compounds. Syntheses were accomplished in an efficient manner by using a ring-closing metathesis (RCM) strategy in a key macrocyclization step. Biological evaluation of these new macrosphelide-based derivatives revealed that several epothilone hybrids, in which a thiazole-containing side chain was incorporated, exhibited potent apoptosis-inducing activity toward human lymphoma cells. These activities were considerably enhanced relative to those of natural macrosphelide compounds. Structure-activity relationship studies revealed that the "ene-dicarbonyl" substructure is apparently essential for bioactivity.
Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Epotilonas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclização , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Epotilonas/síntese química , Epotilonas/química , Epotilonas/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
An efficient and flexible synthesis of poison-frog alkaloids 251O and trans-223B has been achieved by using for both alkaloids an enantiodivergent process starting from the common lactam 1. The relative stereochemistry of 251O and trans-223B was determined to be 7 (R = n-C(7)H(15), R' = n-Pr) and 14 by the present enantioselective synthesis.
Assuntos
Alcaloides/síntese química , Química Orgânica/métodos , Alcaloides de Pirrolizidina/química , Alcaloides/química , Alcenos/química , Animais , Cromatografia Gasosa/métodos , Desenho de Fármacos , Cinética , Modelos Químicos , Venenos/química , Pirróis/química , Ranidae , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , EstereoisomerismoRESUMO
The aim of this study was to examine whether, a new synthesized class of benzocycloalkene derivatives (BCs), enhances apoptosis induced by hyperthermia. The combined effects of hyperthermia (44 degrees C, 20 min) and BCs on apoptosis in human lymphoma U937 cells were investigated. Among the tested compounds (BC1 approximately 9), the combined treatment of 10 muM BC2 or BC4 and hyperthermia showed the largest potency to induce DNA fragmentation at 6 h after hyperthermia. And enhancement of hyperthermia-induced apoptosis by BC2 or BC4 in a dose-dependent manner was observed. When the cells were treated first with BC2 or BC4 at a nontoxic concentration of 20 muM, and exposed to hyperthermia afterwards, a significant enhancement of heat-induced apoptosis was evidenced by DNA fragmentation, morphological changes and phosphatidylserine externalization. Flow cytometry revealed an increase of intracellular superoxide due to BC2 or BC4, which was further increased when hyperthermia was combined. Mitochondrial membrane potential was decreased and the activation of caspase-3 and caspase-8 was enhanced in the cells treated with the combination. The activation of Bid, but no change of Bax and Bcl-2 were observed after the combined treatment. The release of cytochrome c from mitochondria to cytosol, which was induced by hyperthermia, was enhanced by BC2 or BC4. An increase in the intracellular Ca2+ concentration [Ca2+](i), externalization of Fas, and decrease in Hsp70 were observed following the combined treatment. These results indicate that the intracellular superoxide generated by BC2 or BC4 is involved in the enhancement of apoptosis through Fas-mitochondria caspase and [Ca2+](i)-dependent pathways, and a decrease in Hsp70 also contributed to the enhancement of apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Hipertermia Induzida/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/farmacologia , Cálcio/fisiologia , Caspases/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/biossíntese , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Compostos Policíclicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Células U937 , Receptor fas/metabolismoRESUMO
The ability of the derivatives of macrosphelides (MS) core (simplified 16-membered core structure of natural MS) to induce apoptosis in human lymphoma U937 cells was investigated. Of the five compounds examined, MS core with ketones at 8 and 14 positions (MS5) showed the highest potency to induce apoptosis, while another, MS3 with one ketone, was minimal potent. MS5 was found to induce apoptosis in the U937 cells in a time- and dose-dependent fashion, as confirmed by DNA fragmentation analysis. MS5 treated cells showed increase in intracellular reactive oxygen species (ROS), glutathione depletion, Bid activation and lipid peroxidation. Pretreatment of cells with pancaspase inhibitor resulted in the complete inhibition of MS5-induced apoptosis. N-Acetyl-l-cysteine (NAC) pretreatment resulted in the increase in glutathione concentration, reduction of intracellular ROS, complete inhibition of DNA fragmentation, mitochondrial membrane potential (MMP) collapse, Fas externalization and caspase-8 activation. Furthermore, MS5-induced oxidative stress also triggered transient increase in intracellular calcium ion ([Ca2+]i) concentration which was completely inhibited by NAC. Pretreatment with an intracellular Ca2+ chelator, BAPTA-AM reduced MS5-induced DNA fragmentation and caspase-8 activation while it has marginal effects on MMP collapse. Taken together our present data showed that a rapid increase in intracellular ROS by MS5 triggers apoptosis via the Fas/caspase-8-mediated mitochondrial pathway suggesting that the presence of diketone makes the compound more potent to induce apoptosis. These characteristics of MS5 will make it useful for therapeutic applications of targeted apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Compostos Heterocíclicos/farmacologia , Estresse Oxidativo , Receptor fas/metabolismo , Acetilcisteína/farmacologia , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Western Blotting , Citocromos c/metabolismo , Citometria de Fluxo , Glutationa/metabolismo , Humanos , Peroxidação de Lipídeos , Potenciais da Membrana , Espécies Reativas de Oxigênio/metabolismo , Células U937RESUMO
BACKGROUND: The 5,8-disubstituted indolizidines are the largest class of poison-frog alkaloids found in anuran skin, and are of considerable interest because of their inhibitory effects on the neuronal nicotinic acetylcholine receptors. Many synthetic strategies for the construction of this nucleus have been reported: however, a flexible route has not been reported to date. RESULTS: Synthesis of lactam chiral building blocks for the flexible synthesis of the title alkaloids has been achieved using a Michael-type conjugate addition reaction to a chiral cyclic enamine ester as the key step in constructing the trisubstituted piperidine ring system. To demonstrate the usefulness of these chiral building blocks, syntheses of (-)-203A, (-)-205A from 1, and (-)-219F from 2 have been achieved. CONCLUSION: The total synthesis of (-)-203A, (-)-205A, and (-)-219F was achieved, and the absolute stereochemistry of natural 203A was determined to be 5S, 8R, 9S. In addition, the relative stereochemistry of natural 219F was determined.
RESUMO
BACKGROUND: The 5,8-disubstituted indolizidines constitute the largest class of poison-frog alkaloids. Some alkaloids have been shown to act as noncompetitive blockers at nicotinic acetylcholine receptors but the proposed structures and the biological activities of most of the 5,8-disubstituted indolizidines have not been determined because of limited supplies of the natural products. We have therefore conducted experiments to confirm proposed structures and determine biological activities using synthetic compounds. Recently, we reported that one of this class of alkaloids, (-)-235B', acts as a noncompetitive antagonist for α4ß2 nicotinic receptors, and its sensitivity is comparable to that of the classical competitive antagonist for this receptor, dihydro-ß-erythroidine. RESULTS: The enantioselective syntheses of (-)-209B, (-)-231C, (-)-233D, (-)-235B", (-)-221I, and what proved to be an epimer of natural 193E, starting from common chiral lactams have been achieved. When we performed electrophysiological recordings to examine the effects of the synthetic alkaloids on two major subtypes of nicotinic receptors (α4ß2 and α7) expressed in Xenopus laevis oocytes, (-)-231C effectively blocked α4ß2 receptor responses (IC(50 )value, 1.5 µM) with a 7.0-fold higher potency than for blockade of α7 receptor responses. In contrast, synthetic (-)-221I and (-)-epi-193E were more potent in blocking α7 receptor responses (IC(50 )value, 4.4 µM and 9.1 µM, respectively) than α4ß2 receptor responses (5.3-fold and 2.0-fold, respectively). CONCLUSION: We achieved the total synthesis of (-)-209B, (-)-231C, (-)-233D, (-)-235B", (-)-221I, and an epimer of 193E starting from common chiral lactams, and the absolute stereochemistry of natural (-)-233D was determined. Furthermore, the relative stereochemistry of (-)-231C and (-)-221I was also determined. The present asymmetric synthesis of the proposed structure for 193E revealed that the C-8 configuration of natural 193E should be revised. The selectivity for α4ß2 and α7 nicotinic receptors differed markedly for the 5,8-disubstituted indolizidines tested, and thus it appears that the nature of the side chains in these indolizidines is crucial with regard to subtype-selectivity.
RESUMO
Hybrid compounds of macrosphelides and epothilones, both of which are natural macrolides having a 16-membered skeleton, were designed and synthesized using a ring-closing metathesis (RCM) strategy. Some of these hybrids were found to exhibit notable apoptosis-inducing activity against human lymphoma cells with higher potency than parent natural macrosphelides, and to be a promising lead compound for development of a new antitumor agent.
Assuntos
Antineoplásicos/síntese química , Compostos Heterocíclicos/síntese química , Tiazóis/química , Antineoplásicos/química , Ciclização , Compostos Heterocíclicos/químicaRESUMO
Two new phorbol esters, NPB-11 (12-O-methoxymethylphorbol-13-decanoate) and NPB-15 (12-O-benzyloxymethylphorbol-13-decanoate) were synthesized. The compounds exhibited potent anti-HIV-1 activity and low cytotoxicity in MT-4 cells by MTT assay even at a high concentration [50% cytotoxic concentrations (CC50) were 8.32 and 4.39 microg/ml, respectively]. Two inhibitors strongly suppressed HIV-1 (IIIB strain) replication in MT-4 cells with a 50% effective concentration (EC50) of 1.3 and 0.27 ng/ml, respectively. NPB-11 efficiently blocked replication of both X4 and R5 HIV-1 in PHA-activated peripheral blood mononuclear cells and MT-4 cells as revealed by p24 assay. The antiviral activity appeared to be mediated, at least partially, by the down-regulation of the expression of CD4 and the HIV-1 co-receptors, CXCR4 and CCR5. The compounds were also capable of selectively up-regulating HIV-1 expression in a variety of latently infected cell lines and inducing cell death in HIV-1 infected cells. The effect of NPBs on the induction of HIV-1 was specifically blocked by nontoxic doses of a protein kinase C blocker, staurosporine. NPB-11 blocked the spread of HIV-1 released from latently infected ACH-2 cells to MT-4 cells in a co-culture system. When combined with AZT, NPB-11 synergistically inhibited HIV-1 replication in MTT assay using MT-4 cells. These data suggest that these agents might be useful in reducing persistent viral reservoirs in patients and as adjuvant therapy in patients treated with HAART.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Ésteres de Forbol/farmacologia , Ativação Viral/efeitos dos fármacos , Linhagem Celular , Regulação para Baixo , Citometria de Fluxo , HIV-1/fisiologia , Humanos , Replicação Viral/efeitos dos fármacosRESUMO
[reaction: see text] A new total synthesis of macrosphelides A and B using ring-closing metathesis (RCM) as a macrocyclization step is described. The substrate of the RCM could be synthesized from readily available chiral materials, methyl (S)-(+)-3-hydroxybutyrate and methyl (S)-(-)-lactate, with a high efficiency. The RCM proceeded in the presence of Grubbs' Ru-complex, providing a new effective synthetic route to these natural products.
RESUMO
C(2)-symmetric 2,6-diallylpiperidine 1-carboxylic acid methyl ester (5) was examined via the double asymmetric allylboration of glutaraldehyde followed by aminocyclization and carbamation as a promising chiral building block for piperidine-related alkaloids, which were synthesized by the desymmetrization of 5 using intramolecular iodocarbamation as a key step. [reaction: see text]
Assuntos
Alcaloides/síntese química , Ésteres/química , Ésteres/síntese química , Piperidinas/síntese química , Alcaloides/química , Glutaral/química , Estrutura Molecular , Piperidinas/químicaRESUMO
[reaction: see text] A concise and stereoselective synthesis of the chiral building block, dioxanylpiperidene 4 as a precursor for deoxyazasugars, starting from the Garner aldehyde 5 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring is described. The asymmetric synthesis of 1-deoxygalactonojirimycin and its congeners 1-3 was carried out via the use of 4 in a highly stereocontrolled mode.
Assuntos
1-Desoxinojirimicina/química , Piperidinas/química , EstereoisomerismoRESUMO
[structure: see text] Synthesis of alkaloid 223A has been achieved by sequential use of our original conjugate addition reaction to enaminoesters as the key step. The proposed structure for natural 223A (A, absolute configuration unknown) was revised to B, and the relative stereostructure was determined to be 5R*,6R*,8R*,9S* by the present synthesis.
Assuntos
Anuros/metabolismo , Indolizinas/síntese química , Animais , Indicadores e Reagentes , Indolizinas/química , Espectroscopia de Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier , EstereoisomerismoRESUMO
Efficient monocyclic 1,2-diazepine formation via a tandem electrocyclization reaction of cyclobutenones with lithiodiazoacetate is demonstrated. The reaction proceeds through an oxy anion-accelerated 4π-ring opening of cyclobutene followed by an 8π-ring closure of the resultant oxy anion-substituted diazo-diene under mild conditions to furnish a 1,2-diazepine via formal diazomethylene insertion into the C-C bond of cyclobutenone.
Assuntos
Azepinas/síntese química , Ciclobutanos/química , Diazometano/química , Azepinas/química , Diazometano/análogos & derivados , Estrutura MolecularRESUMO
Synthesis of sominone was achieved starting from dehydroepiandrosterone on the basis of an RCM strategy for the construction of a delta-lactone side chain. This synthetic protocol was applied for the synthesis of several analogous derivatives including 1-deoxy-24-norsominone (denosomin), which was revealed to exhibit notable bioactivities for new antidementia chemotherapy, exceeding the original natural compound sominone.