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1.
Chem Commun (Camb) ; 59(98): 14563-14566, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-37986604

RESUMO

Ratiometric Raman analysis of reversible thia-Michael reactions was achieved using α-cyanoacrylic acid (αCNA) derivatives. Among αCNAs, the smallest derivative, ThioRas (molecular weight: 167 g mol-1), and its glutathione adduct were simultaneously detected in various subcellular locations using Raman microscopy.

2.
J Am Chem Soc ; 144(44): 20171-20176, 2022 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-36306265

RESUMO

Visible light, particularly in the blue region of the spectrum, can cause cell dysfunction through the generation of singlet oxygen, contributing to cellular aging and age-related pathologies. Although photooxidation of nucleic acids, lipids, and amino acids has been extensively studied, the magnitude and span of blue-light-induced protein damages within proteome remain largely unknown. Herein we present a chemoproteomic approach to mapping blue-light-damaged proteins in live mammalian cells by exploiting a nucleophilic alkyne chemical probe. A gene ontology enrichment analysis revealed that cell surface proteins are more readily oxidized than other susceptible sets of proteins, including mitochondrial proteins. In particular, the integrin family of cell surface receptors (ITGs) was highly ranked in the mammalian cells tested, including human corneal endothelial cells. The blue-light-oxidized ITGB1 protein was functionally inactive in promoting cell adhesion and proliferation, suggesting that the photodamage of integrins contributes to the blue-light-induced cell dysfunction. Further application of our method to various cells and tissues should lead to a comprehensive analysis of light-sensitive proteins.


Assuntos
Células Endoteliais , Oxigênio Singlete , Animais , Humanos , Oxirredução , Luz , Mamíferos
3.
Curr Opin Chem Biol ; 70: 102181, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35792373

RESUMO

Raman microscopy has been used to deduce information about the distributions of endogenous biomolecules without exogenous labeling. Several functional groups, such as alkynes (CC), nitriles (CN), and carbon-deuterium (C-D) bonds, have been employed in recent years as Raman tags to detect target molecules in cells. In this article, we review some recent advances in applications using deuterated fatty acids for lipid analysis, such as investigation of tumor-selective cytotoxicity of γ-linolenic acid (GLA), simultaneous two-color imaging of stearate and oleate using deuterated and protonated alkynes, Raman hyperspectral imaging, and analyses of the physical properties of lipids through spectral unmixing of the C-D vibrational frequencies. In addition, we review some advanced methods for observing intracellular metabolic activities, such as de novo lipogenesis from deuterium-labeled precursors.


Assuntos
Ácido Oleico , Estearatos , Alcinos/química , Carbono , Deutério/química , Ácidos Graxos/metabolismo , Nitrilas , Ácido Oleico/metabolismo , Análise Espectral Raman , Ácido gama-Linolênico
4.
J Org Chem ; 86(23): 16249-16258, 2021 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-34784214

RESUMO

16,17-Dihydroheronamide C (8) and ent-heronamide C (ent-1) were designed as probes for the mode-of-action analysis of heronamide C (1). These molecules were synthesized by utilizing a highly modular strategy developed in the preceding paper. The evaluation of the antifungal activity of these compounds revealed the exceptional importance of the C16-C17 double bond for the antifungal activity of heronamide C and the existence of chiral recognition between heronamide C (1) and cell membrane components.


Assuntos
Antifúngicos , Antifúngicos/farmacologia , Lactamas Macrocíclicas , Relação Estrutura-Atividade
5.
Org Biomol Chem ; 19(38): 8232-8236, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34528645

RESUMO

Alkynes were employed as tags to observe small molecules in cells by Raman microscopy. Herein, simple deuteration was found to shift the vibrational frequency of the alkyne by 135 cm-1. Two-color Raman imaging of D-alkynes and H-alkynes made it possible to distinguish between and observe similar small molecules in live cells.


Assuntos
Alcinos
6.
Chem Commun (Camb) ; 57(17): 2180-2183, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33527102

RESUMO

γ-Linolenic acid (GLA) is reported to show tumor-selective cytotoxicity through unidentified mechanisms. Here, to assess the involvement of oxidized metabolites of GLA, we synthesized several deuterated GLAs and evaluated their metabolism and cytotoxicity towards normal human fibroblast WI-38 cells and VA-13 tumor cells generated from WI-38 by transformation with SV40 virus. Deuteration of GLA suppressed both metabolism and cytotoxicity towards WI-38 cells and increased the selectivity for VA-13 cells. Fully deuterated GLA was visualized by Raman imaging, which indicated that GLA is accumulated in intracellular lipid droplets of VA-13 cells. Our results suggest the tumor-selective cytotoxicity is due to GLA itself, not its oxidized metabolites.


Assuntos
Ácido gama-Linolênico/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Deutério , Fibroblastos/efeitos dos fármacos , Humanos , Estrutura Molecular , Análise Espectral Raman
7.
Sci Rep ; 10(1): 5333, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210301

RESUMO

In plants, stomata regulate water loss through transpiration for plant growth and survival in response to various environmental stressors; and simple methods to assess stomatal dynamics are needed for physiological studies. Herein, we report a fluorescence-imaging-based method using fluorescein diacetate tagged with Hoechst 33342, a nuclear staining chemical probe (HoeAc2Fl) for the qualitative assessment of stomatal dynamics. In our method, the stomatal movement is inferred by simple monitoring of the fluorescence intensity in the nucleus of the stomata.


Assuntos
Fluoresceínas/química , Imagem Óptica/métodos , Estômatos de Plantas/fisiologia , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Dióxido de Carbono/metabolismo , Fluorescência , Corantes Fluorescentes/química , Regulação da Expressão Gênica de Plantas/genética , Folhas de Planta/metabolismo , Estômatos de Plantas/metabolismo , Transpiração Vegetal/fisiologia , Água/metabolismo
8.
Chemistry ; 25(70): 16002-16006, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31625215

RESUMO

Despite the potential of α-fluoroethers in medicinal chemistry, their synthetic methods, especially etherification of aliphatic alcohols, have been limited. Herein, we developed two- and three-step gem-difluoropropargylation of aliphatic alcohols including amino acid derivatives and naturally occurring bioactive molecules. Highly chemoselective etherification proceeded by using the gem-difluoropropargyl bromide dicobalt complex in the presence of silver triflate and triethylamine. Decomplexation of dicobalt complexes was achieved by using cerium ammonium nitrate or N,N,N'-trimethylethylenediamine. The thus obtained gem-difluoropropargyl ethers were converted to various α-difluoroethers which are expected to be useful for medicinal chemistry.

9.
Nat Commun ; 9(1): 3654, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30194307

RESUMO

The phytohormone 7-iso-(+)-jasmonoyl-L-isoleucine (JA-Ile) mediates plant defense responses against herbivore and pathogen attack, and thus increases plant resistance against foreign invaders. However, JA-Ile also causes growth inhibition; and therefore JA-Ile is not a practical chemical regulator of plant defense responses. Here, we describe the rational design and synthesis of a small molecule agonist that can upregulate defense-related gene expression and promote pathogen resistance at concentrations that do not cause growth inhibition in Arabidopsis. By stabilizing interactions between COI1 and JAZ9 and JAZ10 but no other JAZ isoforms, the agonist leads to formation of JA-Ile co-receptors that selectively activate the JAZ9-EIN3/EIL1-ORA59 signaling pathway. The design of a JA-Ile agonist with high selectivity for specific protein subtypes may help promote the development of chemical regulators that do not cause a tradeoff between growth and defense.


Assuntos
Proteínas de Arabidopsis/metabolismo , Ciclopentanos/agonistas , Resistência à Doença/efeitos dos fármacos , Isoleucina/análogos & derivados , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Arabidopsis , Simulação por Computador , Ciclopentanos/metabolismo , Proteínas de Ligação a DNA , Defensinas/metabolismo , Desenho de Fármacos , Isoleucina/agonistas , Oxilipinas/metabolismo , Fatores de Terminação de Peptídeos/metabolismo , Estereoisomerismo , Fatores de Transcrição/metabolismo
10.
Plant Physiol ; 177(4): 1704-1716, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29934297

RESUMO

Plant root systems are indispensable for water uptake, nutrient acquisition, and anchoring plants in the soil. Previous studies using auxin inhibitors definitively established that auxin plays a central role regulating root growth and development. Most auxin inhibitors affect all auxin signaling at the same time, which obscures an understanding of individual events. Here, we report that jasmonic acid (JA) functions as a lateral root (LR)-preferential auxin inhibitor in Arabidopsis (Arabidopsis thaliana) in a manner that is independent of the JA receptor, CORONATINE INSENSITIVE1 (COI1). Treatment of wild-type Arabidopsis with either (-)-JA or (+)-JA reduced primary root length and LR number; the reduction of LR number was also observed in coi1 mutants. Treatment of seedlings with (-)-JA or (+)-JA suppressed auxin-inducible genes related to LR formation, diminished accumulation of the auxin reporter DR5::GUS, and inhibited auxin-dependent DII-VENUS degradation. A structural mimic of (-)-JA and (+)-coronafacic acid also inhibited LR formation and stabilized DII-VENUS protein. COI1-independent activity was retained in the double mutant of transport inhibitor response1 and auxin signaling f-box protein2 (tir1 afb2) but reduced in the afb5 single mutant. These results reveal JAs and (+)-coronafacic acid to be selective counter-auxins, a finding that could lead to new approaches for studying the mechanisms of LR formation.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Ciclopentanos/metabolismo , Ácidos Indolacéticos/metabolismo , Oxilipinas/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Ciclopentanos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Indenos/farmacologia , Oxilipinas/farmacologia , Reguladores de Crescimento de Plantas/metabolismo , Raízes de Plantas/genética , Plantas Geneticamente Modificadas , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Transdução de Sinais
11.
Org Biomol Chem ; 16(18): 3348-3352, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29520403

RESUMO

We previously reported that coronatine, a virulence factor of plant bacteria, facilitates bacterial infection through an ER (endoplasmic reticulum)-mediated, non-canonical mechanism in the model dicot plant, Arabidopsis thaliana. Here, we report that this same ER-mechanism is ubiquitous among dicots and monocots, and works by affecting the ethylene signaling pathway widely found in plants. The subcellular localization of coronatine by the alkyne-tag Raman imaging (ATRI) approach provided a convincing clue.


Assuntos
Aminoácidos/análise , Toxinas Bacterianas/análise , Commelina/microbiologia , Indenos/análise , Doenças das Plantas/microbiologia , Análise Espectral Raman/métodos , Alcinos/química , Arabidopsis/química , Arabidopsis/microbiologia , Commelina/química , Retículo Endoplasmático/química , Retículo Endoplasmático/microbiologia , Simulação de Acoplamento Molecular
12.
ACS Cent Sci ; 3(5): 462-472, 2017 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-28573209

RESUMO

Coronatine (1), a small-molecular virulence factor produced by plant-pathogenic bacteria, promotes bacterial infection by inducing the opening of stomatal pores, the major route of bacterial entry into the plant, via the jasmonate-mediated COI1-JAZ signaling pathway. However, this pathway is also important for multiple plant functions, including defense against wounding by herbivorous insects. Thus, suppression of the COI1-JAZ signaling pathway to block bacterial infection would concomitantly impair plant defense against herbivorous wounding. Here, we report additional, COI1-JAZ-independent, action of 1 in Arabidopsis thaliana guard cells. First, we found that a stereoisomer of 1 regulates the movement of Arabidopsis guard cells without affecting COI1-JAZ signaling. Second, we found using alkyne-tagged Raman imaging (ATRI) that 1 is localized to the endoplasmic reticulum (ER) of living guard cells of Arabidopsis. The use of arc6 mutant lacking chloroplast formation was pivotal to circumvent the issue of autofluorescence during ATRI. These findings indicate that 1 has an ER-related action on Arabidopsis stomata that bypasses the COI1-JAZ signaling module. It may be possible to suppress the action of 1 on stomata without impairing plant defense responses against herbivores.

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