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1.
Cell Rep ; 37(3): 109846, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34686324

RESUMO

Optical methods for measuring intracellular ions including Ca2+ revolutionized our understanding of signal transduction. However, these methods are not extensively applied to intact organs due to issues including inner filter effects, motion, and available probes. Mitochondrial Ca2+ is postulated to regulate cell energetics and death pathways that are best studied in an intact organ. Here, we develop a method to optically measure mitochondrial Ca2+ and demonstrate its validity for mitochondrial Ca2+ and metabolism using hearts from wild-type mice and mice with germline knockout of the mitochondria calcium uniporter (MCU-KO). We previously reported that germline MCU-KO hearts do not show an impaired response to adrenergic stimulation. We find that these MCU-KO hearts do not take up Ca2+, consistent with no alternative Ca2+ uptake mechanisms in the absence of MCU. This approach can address the role of mitochondrial Ca2+ to the myriad of functions attributed to alterations in mitochondrial Ca2+.

2.
J Mol Cell Cardiol ; 144: 87-96, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32442661

RESUMO

AIMS: In cardiomyocytes, there is microRNA (miR) in the mitochondria that originates from the nuclear genome and matures in the cytoplasm before translocating into the mitochondria. Overexpression of one such miR, miR-181c, can lead to heart failure by stimulating reactive oxygen species (ROS) production and increasing mitochondrial calcium level ([Ca2+]m). Mitochondrial calcium uptake 1 protein (MICU1), a regulatory protein in the mitochondrial calcium uniporter complex, plays an important role in regulating [Ca2+]m. Obesity results in miR-181c overexpression and a decrease in MICU1. We hypothesize that lowering miR-181c would protect against obesity-induced cardiac dysfunction. METHODS AND RESULTS: We used an in vivo mouse model of high-fat diet (HFD) for 18 weeks and induced high lipid load in H9c2 cells with oleate-conjugated bovine serum albumin in vitro. We tested the cardioprotective role of lowering miR-181c by using miR-181c/d-/- mice (in vivo) and AntagomiR against miR-181c (in vitro). HFD significantly upregulated heart levels of miR-181c and led to cardiac hypertrophy in wild-type mice, but not in miR-181c/d-/- mice. HFD also increased ROS production and pyruvate dehydrogenase activity (a surrogate for [Ca2+]m), but the increases were alleviated in miR-181c/d-/- mice. Moreover, miR-181c/d-/- mice fed a HFD had higher levels of MICU1 than did wild-type mice fed a HFD, attenuating the rise in [Ca2+]m. Overexpression of miR-181c in neonatal ventricular cardiomyocytes (NMVM) caused increased ROS production, which oxidized transcription factor Sp1 and led to a loss of Sp1, thereby slowing MICU1 transcription. Hence, miR-181c increases [Ca2+]m through Sp1 oxidation and downregulation of MICU1, suggesting that the cardioprotective effect of miR-181c/d-/- results from inhibition of Sp1 oxidation. CONCLUSION: This study has identified a unique nuclear-mitochondrial communication mechanism in the heart orchestrated by miR-181c. Obesity-induced overexpression of miR-181c increases [Ca2+]m via downregulation of MICU1 and leads to cardiac injury. A strategy to inhibit miR-181c in cardiomyocytes can preserve cardiac function during obesity by improving mitochondrial function. Altering miR-181c expression may provide a pharmacologic approach to improve cardiomyopathy in individuals with obesity/type 2 diabetes.


Assuntos
Núcleo Celular/metabolismo , MicroRNAs/genética , Mitocôndrias Cardíacas/metabolismo , Obesidade/genética , Obesidade/metabolismo , Disfunção Ventricular/etiologia , Disfunção Ventricular/metabolismo , Animais , Biomarcadores , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Camundongos , Camundongos Knockout , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Miócitos Cardíacos/metabolismo , Obesidade/complicações , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição Sp1/metabolismo , Disfunção Ventricular/fisiopatologia
3.
Acta Physiol (Oxf) ; 228(2): e13358, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31385408

RESUMO

AIM: Myocardial ischaemia/reperfusion (I/R) produces structural and functional alterations depending on the duration of ischaemia. Brief ischaemia followed by reperfusion causes reversible contractile dysfunction (stunned heart) but long-lasting ischaemia followed by reperfusion can result in irreversible injury with cell death. Events during I/R can alter endoplasmic reticulum (ER) function leading to the accumulation of unfolded/misfolded proteins. The resulting ER stress induces activation of several signal transduction pathways, known as unfolded protein response (UPR). Experimental evidence shows that UPR contributes to cell death in irreversible I/R injury; however, there is still uncertainty for its occurrence in the stunned myocardium. This study investigated the ER stress response and its functional impact on the post-ischaemic cardiac performance of the stunned heart. METHODS: Perfused rat hearts were subjected to 20 minutes of ischaemia followed by 30 minutes of reperfusion. UPR markers were evaluated by qRT-PCR and western blot. Post-ischaemic mechanical recovery was measured in absence and presence of two chemical chaperones: tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA). RESULTS: Analysis of mRNA and protein levels of various ER stress effectors demonstrated that different UPR signalling cascades, involving both pro-survival and pro-apoptotic pathways, are activated. Inhibition of the UPR with chemical chaperones improved the post-ischaemic recovery of cardiac mechanical function without affecting the I/R-induced increase in oxidative stress. CONCLUSION: Our results suggest that prevention of ER stress by chemical chaperones could be a therapeutic tool to limit deterioration of the contractile function in clinical settings in which the phenomenon of myocardial stunning is present.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio Atordoado/tratamento farmacológico , Miocárdio/metabolismo , Fenilbutiratos/farmacologia , Ácido Tauroquenodesoxicólico/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Colagogos e Coleréticos/farmacologia , Modelos Animais de Doenças , Proteínas de Choque Térmico/metabolismo , Masculino , Miocárdio Atordoado/etiologia , Miocárdio Atordoado/patologia , Miocárdio/patologia , Ratos , Ratos Wistar , Transdução de Sinais , Resposta a Proteínas não Dobradas
4.
J Am Heart Assoc ; 8(24): e012919, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31801413

RESUMO

Background Translocation of miR-181c into cardiac mitochondria downregulates the mitochondrial gene, mt-COX1. miR-181c/d-/- hearts experience less oxidative stress during ischemia/reperfusion (I/R) and are protected against I/R injury. Additionally, miR-181c overexpression can increase mitochondrial matrix Ca2+ ([Ca2+]m), but the mechanism by which miR-181c regulates [Ca2+]m is unknown. Methods and Results By RNA sequencing and analysis, here we show that hearts from miR-181c/d-/- mice overexpress nuclear-encoded Ca2+ regulatory and metabolic pathway genes, suggesting that alterations in miR-181c and mt-COX1 perturb mitochondria-to-nucleus retrograde signaling and [Ca2+]m regulation. Quantitative polymerase chain reaction validation of transcription factors that are known to initiate retrograde signaling revealed significantly higher Sp1 (specificity protein) expression in the miR-181c/d-/- hearts. Furthermore, an association of Sp1 with the promoter region of MICU1 was confirmed by chromatin immunoprecipitation-quantitative polymerase chain reaction and higher expression of MICU1 was found in the miR-181c/d-/- hearts. Conversely, downregulation of Sp1 by small interfering RNA decreased MICU1 expression in neonatal mouse ventricular myocytes. Changes in PDH activity provided evidence for a change in [Ca2+]m via the miR-181c/MICU1 axis. Moreover, this mechanism was implicated in the pathology of I/R injury. When MICU1 was knocked down in the miR-181c/d-/- heart by lentiviral expression of a short-hairpin RNA against MICU1, cardioprotective effects against I/R injury were abrogated. Furthermore, using an in vitro I/R model in miR-181c/d-/- neonatal mouse ventricular myocytes, we confirmed the contribution of both Sp1 and MICU1 in ischemic injury. Conclusions miR-181c regulates mt-COX1, which in turn regulates MICU1 expression through the Sp1-mediated mitochondria-to-nucleus retrograde pathway. Loss of miR-181c can protect the heart from I/R injury by modulating [Ca2+]m through the upregulation of MICU1.


Assuntos
Proteínas de Ligação ao Cálcio/fisiologia , Cálcio/metabolismo , MicroRNAs/fisiologia , Mitocôndrias Cardíacas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
5.
Am J Physiol Heart Circ Physiol ; 317(5): H1116-H1124, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31625778

RESUMO

Vascular stiffness plays a key role in the pathogenesis of hypertension. Recent studies indicate that the age-associated reduction in miR-181b levels in vascular smooth muscle cells (VSMCs) contributes to increased vascular stiffness. As these findings suggest that inhibiting degradation of miR-181b might prevent vascular stiffening, we have assessed whether the microRNA-degrading translin/trax (TN/TX) complex mediates degradation of miR-181b in the aorta.We found that TN-/- mice display elevated levels of miR-181b expression in the aorta. Therefore, we tested whether TN deletion prevents vascular stiffening in a mouse model of hypertension, induced by chronic high-salt intake (4%NaCl in drinking water for 3 wk; HSW). TN-/- mice subjected to HSW stress do not show increased vascular stiffness, as monitored by pulse wave velocity and tensile testing. The protective effect of TN deletion in the HSW paradigm appears to be mediated by its ability to increase miR-181b in the aorta since HSW decreases levels of miR-181b in WT mice, but not in TN KO mice. We demonstrate for the first time that interfering with microRNA degradation can have a beneficial impact on the vascular system and identify the microRNA-degrading TN/TX RNase complex as a potential therapeutic target in combatting vascular stiffness.NEW & NOTEWORTHY While the biogenesis and mechanism of action of mature microRNA are well understood, much less is known about the regulation of microRNA via degradation. Recent studies have identified the protein complex, translin(TN)/trax(TX), as a microRNA-degrading enzyme. Here, we demonstrate that TN/TX is expressed in vascular smooth muscle cells. Additionally, deletion of the TN/TX complex selectively increases aortic miR-181b and prevents increased vascular stiffness caused by ingestion of high-salt water. To our knowledge, this is first report describing the role of a microRNA RNAse in cardiovascular biology or pathobiology.


Assuntos
Aorta/enzimologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/metabolismo , Hipertensão/enzimologia , MicroRNAs/metabolismo , Rigidez Vascular , Animais , Aorta/fisiopatologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Deleção de Genes , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Estabilidade de RNA , Proteínas de Ligação a RNA/genética , Cloreto de Sódio na Dieta , Regulação para Cima
6.
Molecules ; 24(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500119

RESUMO

Ionic liquids based on different l-amino acids (glycine, l-valine, l-leucine, l-isoleucine, l-histidine, l-methionine, l-tyrosine, l-tryptophan, l-arginine, and l-threonine) and different cations (tetrabutylammonium (TBA), tributylmethylammonium (tBMA), didecyldimethylammonium (DDA), (2-hydroxyethyl)trimethylammonium (choline) (Chol), alkyl(C12-C14) dimethylbenzylammonium (benzalkonium) (BA), dodecyltrimethylammonium (DDTMA), hexadecyltrimethylammonium (HDTMA), octadecyltrimethylammonium (ODTMA) and 1-ethyl-3-methylimidazolium (EMIM)) have been synthesized and characterized by NMR and FTIR. Viscosity, specific rotation, surface activity, thermal stability (TG), and phase transformations (DSC) have been determined and compared with available data. Furthermore, benzalkonium, didecyldimethylammonium, dodecyltrimethylammonium, hexadecyltrimethylammonium, and octadecyltrimethylammonium amino acid ionic liquids have been shown to exhibit surface activity. The dissolution of cellulose in amino acid ionic liquids (AAILs) composed of various cations was also investigated. Cellulose was only dissolved in EMIM salts of amino acids. In particular, the influence of the cation type on selected physicochemical and spectroscopic properties were discussed. The article is a mini review on amino acid ionic liquids.


Assuntos
Aminoácidos/química , Imidazóis/química , Líquidos Iônicos/química , Compostos de Amônio Quaternário/química , Cátions/química , Celulose/química , Espectroscopia de Ressonância Magnética , Relação Estrutura-Atividade
7.
J Clin Invest ; 129(11): 4708-4723, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393856

RESUMO

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers.


Assuntos
Reprogramação Celular , Mutação , Proteínas de Neoplasias/metabolismo , Neoplasias , Fosfoproteínas , Proteoma/metabolismo , Fatores de Processamento de RNA , Serina , Transcriptoma , Animais , Linhagem Celular Tumoral , Metabolismo Energético/genética , Glicina , Humanos , Camundongos , Proteínas de Neoplasias/genética , Neoplasias/dietoterapia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fosfoglicerato Desidrogenase/genética , Fosfoglicerato Desidrogenase/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteoma/genética , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Arch Biochem Biophys ; 666: 52-62, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30935885

RESUMO

Over two thousand proteins are found in the mitochondrial compartment but the mitochondrial genome codes for only 13 proteins. The majority of mitochondrial proteins are products of nuclear genes and are synthesized in the cytosol, then translocated into the mitochondria. Most of the subunits of the five respiratory chain complexes in the inner mitochondrial membrane, which generate a proton gradient across the membrane and produce ATP, are encoded by nuclear genes. Therefore, it is quite clear that import of nuclear-encoded proteins into the mitochondria is essential for mitochondrial function. Nuclear to mitochondrial communication is well studied. However, there is another arm to this communication, mitochondria to nucleus retrograde signaling. This plays an important role in the maintenance of cellular homeostasis, and is less well studied. Several transcription factors, including Sp1, SIRT3 and GSP2, are activated by altered mitochondrial function. These activated transcription factors then translocate to the nucleus. Based on the mitochondrially generated molecular signal, nuclear genes are targeted, which alters transcription of nuclear genes that code for mitochondrial proteins. This review article will mainly focus on this interactive and bi-directional communication between mitochondria and nucleus, and how this communication plays a significant role in muscle cell biology.


Assuntos
Núcleo Celular/metabolismo , Mitocôndrias Musculares/metabolismo , Músculos/citologia , Animais , Sinalização do Cálcio , Homeostase , Humanos , Proteínas Mitocondriais/metabolismo , Músculos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
9.
Front Physiol ; 9: 1291, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30298016

RESUMO

Abnormal mitochondrial calcium ([Ca2+]m) handling and energy deficiency results in cellular dysfunction and cell death. Recent studies suggest that nuclear-encoded microRNAs (miRNA) are able to translocate in to the mitochondrial compartment, and modulate mitochondrial activities, including [Ca2+]m uptake. Apart from this subset of miRNAs, there are several miRNAs that have been reported to target genes that play a role in maintaining [Ca2+]m levels in the cytoplasm. It is imperative to validate miRNAs that alter [Ca2+]m handling, and thereby alter cellular fate. The focus of this review is to highlight the mitochondrial miRNAs (MitomiRs), and other cytosolic miRNAs that target mRNAs which play an important role in [Ca2+]m handling.

10.
Magn Reson Chem ; 55(3): 169-176, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26132551

RESUMO

Complete and unambiguous 1 H NMR chemical shift assignment of α-cedrene (2) and cedrol (9), as well as for α-pipitzol (1), isocedrol (10), and the six related compounds 3-8 has been established by iterative full spin analysis using the PERCH NMR software (PERCH Solutions Ltd., Kuopio, Finland). The total sets of coupling constants are described and correlated with the conformational equilibria of the five-membered ring of 1-10, which were calculated using the complete basis set method. Copyright © 2015 John Wiley & Sons, Ltd.


Assuntos
Sesquiterpenos/química , Terpenos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Sesquiterpenos Policíclicos , Software
11.
Am J Physiol Heart Circ Physiol ; 311(3): H713-24, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27422983

RESUMO

Previous results from our laboratory showed that phosphorylation of ryanodine receptor 2 (RyR2) by Ca(2+) calmodulin-dependent kinase II (CaMKII) was a critical but not the unique event responsible for the production of reperfusion-induced arrhythmogenesis, suggesting the existence of other mechanisms cooperating in an additive way to produce these rhythm alterations. Oxidative stress is a prominent feature of ischemia/reperfusion injury. Both CaMKII and RyR2 are proteins susceptible to alteration by redox modifications. This study was designed to elucidate whether CaMKII and RyR2 redox changes occur during reperfusion and whether these changes are involved in the genesis of arrhythmias. Langendorff-perfused hearts from rats or transgenic mice with genetic ablation of CaMKII phosphorylation site on RyR2 (S2814A) were subjected to ischemia-reperfusion in the presence or absence of a free radical scavenger (mercaptopropionylglycine, MPG) or inhibitors of NADPH oxidase and nitric oxide synthase. Left ventricular contractile parameters and monophasic action potentials were recorded. Oxidation and phosphorylation of CaMKII and RyR2 were assessed. Increased oxidation of CaMKII during reperfusion had no consequences on the level of RyR2 phosphorylation. Avoiding the reperfusion-induced thiol oxidation of RyR2 with MPG produced a reduction in the number of arrhythmias and did not modify the contractile recovery. Conversely, selective prevention of S-nitrosylation and S-glutathionylation of RyR2 was associated with higher numbers of arrhythmias and impaired contractility. In S2814A mice, treatment with MPG further reduced the incidence of arrhythmias. Taken together, the results suggest that redox modification of RyR2 synergistically with CaMKII phosphorylation modulates reperfusion arrhythmias.


Assuntos
Arritmias Cardíacas/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Contração Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Potenciais de Ação , Animais , Arritmias Cardíacas/metabolismo , Western Blotting , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/efeitos dos fármacos , Eletroforese , Sequestradores de Radicais Livres/farmacologia , Glutationa/metabolismo , Preparação de Coração Isolado , Masculino , Camundongos , Camundongos Transgênicos , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/metabolismo , NADPH Oxidases/antagonistas & inibidores , Óxido Nítrico Sintase/antagonistas & inibidores , Oxirredução , Estresse Oxidativo , Fosforilação , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , Tiopronina/farmacologia
13.
Chirality ; 25(12): 939-51, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24151034

RESUMO

The reliability of vibrational circular dichroism (VCD) spectroscopy to discriminate four diastereomeric cedranol acetates 1-4 by means of their absolute configuration is examined. The usage of CompareVOA software to quantify comparisons of the measured infrared (IR) and VCD spectra with the corresponding simulated spectra at the B3LYP/DGDZVP and B3PW91/DGDZVP levels of theory for each diastereomer enabled the B3PW91 functional to be qualified as superior to the B3LYP functional for vibrational calculations of 1-4. Analogously, a set of quantitative VCD spectra cross-comparisons of 1-4 unambiguously distinguished the diastereomers using B3PW91 and failed using B3LYP. Remarkably, quantitative IR spectra cross-comparisons of 1-4 using B3PW91 or B3LYP functionals demonstrated that the achiral spectroscopic IR technique is not able to distinguish cedranol acetate diastereomers. VCD comparisons using anisotropy g-factor values of bands in the 1550-950 cm(-1) region of the spectra were of aid to facilitate visual spectra matching for each diastereomer.

14.
Phytochemistry ; 87: 96-101, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23257707

RESUMO

The chemical investigation of specimens of the Jamaican brown alga Stypopodium zonale led to the isolation of a cytotoxic compound, zonaquinone acetate (1), along with known compounds flabellinone, not previously identified in S. zonale, stypoldione, 5',7'-dihydroxy-2'-pentadecylchromone and sargaol. The structures of the metabolites were established by analysis of the spectral data including 1D and 2D NMR experiments while the stereochemistry of 1 was assessed by VCD measurements. Cytotoxic activity was reported in vitro for 1 against breast cancer and colon cancer cell lines at IC(50) values of 19.22-21.62 µM and 17.11-18.35 µM respectively, comparing favorably with standard treatments tamoxifen (17.22-17.32 µM) and fluorouracil (27.03-31.48 µM). When tested with liver cancer cells (Hep G2), no activity was observed. Weak antioxidant activity was observed with 1 but sargaol exhibited high activity.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Feófitas/química , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/farmacologia , Humanos , Terpenos/química , Terpenos/farmacologia
15.
J Nat Prod ; 75(4): 669-76, 2012 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-22462772

RESUMO

Lupane triterpenoids 2 and 5-12 and oleanene derivatives 13 and 14 were prepared from lupeol (1), betulin (3), and germanicol (4). They were tested for anti-HIV activity, and some structure-activity relationships were outlined. The 20-(S) absolute configuration of epoxylupenone (8) was assessed by comparison of the observed and DFT-calculated vibrational circular dichroism spectra. The CompareVOA algorithm was employed to support the C-20 configuration assignment. The 20,29 double bond in lupenone (2) and 3-epilupeol (15) was stereoselectively epoxidized to produce 20-(S)-8 and 20-(S)-16, respectively, an assignment in agreement with their X-ray diffraction structures.


Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Triterpenos/síntese química , Triterpenos/farmacologia , Fármacos Anti-HIV/química , Dicroísmo Circular , Cristalografia por Raios X , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Triterpenos/química
16.
Chirality ; 24(2): 147-54, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22180246

RESUMO

The use of vibrational circular dichroism spectroscopy for the chiral recognition of the two epimers of 6-cedrol, tricyclic sesquiterpenes, which contains oxygen as the heaviest atom, is shown. Bands in the 1500-850 cm(-1) region of the spectra were analyzed to calculate the anisotropy factors (g), which provided the regions of maximum circular dichroism effect for each epimer.


Assuntos
Terpenos/química , Anisotropia , Dicroísmo Circular , Conformação Molecular , Sesquiterpenos Policíclicos , Estereoisomerismo
17.
J Org Chem ; 75(6): 1898-910, 2010 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-20180516

RESUMO

The regioisomeric alpha-cyano ketene-O,O-dialkyl acetals 2a-e and 4a-e, sequential intermediates in the diazomethane induced conversion of indole alpha-cyano-gamma-lactones 1a-e to 2-indolyl cyanomalonates 5a-e, were isolated and characterized. Formation of the steady-state intermediate cycloprop[b]indoles 3a-e was evidenced by means of NMR and confirmed by the X-ray structure of 3c, demonstrating that the formation of 5a-e from 2a-e proceeds through two consecutive and one parallel unimolecular steps, with intermediates 3a-e formed in reversible processes. Evidence that the reversible reactions proceed via [1,3]-rearrangements is presented. The steady-state kinetic approach applied to intermediate 3 allowed a minimal two consecutive step 2 --> 4--> 5 kinetic model, in which the steric bulkiness of the alkyl substituent affects strongly the associated rate constants, k(1) and k(2), inverting the rate-determining step. The solvation effects enhanced the feasibility of these skeletal rearrangements as they stabilized the transition states to a great extent. The experimental determined thermodynamic parameters and DFT calculations suggest that these cascade rearrangements occur through [1,3]-sigmatropic mechanisms, in which asynchronous bond reorganization processes via four membered pseudopericyclic transition states are highly favorable.


Assuntos
Acetais/química , Etilenos/química , Cetonas/química , Oxigênio/química , Teoria Quântica , Cristalografia por Raios X , Diazometano/química , Cinética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Termodinâmica
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