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1.
Molecules ; 26(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064783

RESUMO

All over the world, societies are facing rapidly aging populations combined with a growing number of patients suffering from Alzheimer's disease (AD). One focus in pharmaceutical research to address this issue is on the reduction of the longer amyloid-ß (Aß) fragments in the brain by modulation of γ-secretase, a membrane-bound protease. R-Flurbiprofen (tarenflurbil) was studied in this regard but failed to show significant improvement in AD patients in a phase 3 clinical trial. This was mainly attributed to its low ability to cross the blood-brain barrier (BBB). Here, we present the synthesis and in vitro evaluation of a racemic meta-carborane analogue of flurbiprofen. By introducing the carborane moiety, the hydrophobicity could be shifted into a more favourable range for the penetration of the blood-brain barrier, evident by a logD7.4 value of 2.0. Furthermore, our analogue retained γ-secretase modulator activity in comparison to racemic flurbiprofen in a cell-based assay. These findings demonstrate the potential of carboranes as phenyl mimetics also in AD research.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Compostos de Boro/farmacologia , Flurbiprofeno/análogos & derivados , Compostos de Boro/síntese química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase/farmacologia , Flurbiprofeno/química , Humanos , Concentração Inibidora 50
2.
Molecules ; 26(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807680

RESUMO

N,N'-chelate organoboron compounds have been successfully applied in bioimaging, organic light-emitting diodes (OLEDs), functional polymer, photocatalyst, electroluminescent (EL) devices, and other science and technology areas. However, the concise and efficient synthetic methods become more and more significant for material science, biomedical research, or other practical science. Here, we summarized the organoboron-N,N'-chelate derivatives and showed the different routes of their syntheses. Traditional methods to synthesize N,N'-chelate organoboron compounds were mainly using bidentate ligand containing nitrogen reacting with trivalent boron reagents. In this review, we described a series of bidentate ligands, such as bipyridine, 2-(pyridin-2-yl)-1H-indole, 2-(5-methyl-1H-pyrrol-2-yl)quinoline, N-(quinolin-8-yl)acetamide, 1,10-phenanthroline, and diketopyrrolopyrrole (DPP).


Assuntos
Compostos de Boro/síntese química , Indóis/química , Piridinas/química , Quinolinas/química , Isocianatos/química , Ligantes , Fenantrolinas/química
3.
Molecules ; 26(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916755

RESUMO

The development of novel, tumor-selective and boron-rich compounds as potential agents for use in boron neutron capture therapy (BNCT) represents a very important field in cancer treatment by radiation therapy. Here, we report the design and synthesis of two promising compounds that combine meta-carborane, a water-soluble monosaccharide and a linking unit, namely glycine or ethylenediamine, for facile coupling with various tumor-selective biomolecules bearing a free amino or carboxylic acid group. In this work, coupling experiments with two selected biomolecules, a coumarin derivative and folic acid, were included. The task of every component in this approach was carefully chosen: the carborane moiety supplies ten boron atoms, which is a tenfold increase in boron content compared to the l-boronophenylalanine (l-BPA) presently used in BNCT; the sugar moiety compensates for the hydrophobic character of the carborane; the linking unit, depending on the chosen biomolecule, acts as the connection between the tumor-selective component and the boron-rich moiety; and the respective tumor-selective biomolecule provides the necessary selectivity. This approach makes it possible to develop a modular and feasible strategy for the synthesis of readily obtainable boron-rich agents with optimized properties for potential applications in BNCT.


Assuntos
Compostos de Boro/síntese química , Cumarínicos/química , Ácido Fólico/química , Aminas/química , Compostos de Boro/química , Ácidos Carboxílicos/química , Glicina/química
5.
Anal Bioanal Chem ; 413(9): 2529-2541, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33712915

RESUMO

Fluorescent probes with outstanding physical and biological properties are superior for functional fluorescent dyes design. However, few studies pay attention to the stability of specific groups in fluorescent probes. The aldehyde group in the fluorescent probe is highly active but unstable under certain conditions. Therefore, we introduced ethoxy groups to realize the conversion to aldehyde groups under acidic conditions and avoid the instability of straightforward aldehyde groups. In this work, two fluorophores based on the multi acetal difluoroboraindacene (BODIPY) units with combination of the pharmaceutical intermediate chalcone have been firstly developed. In the design part, chalcone was introduced as a medium for fluorophore and multiple acetal. The mild synthesis strategy is based on the ligand ((Z)-2-chloro-1-(difluoroboranyl)-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)(phenyl)methyl)-1H-pyrrole) and connects with chalcone in (2E,2'E)-3,3'-(1,3-phenylene)bis(1-(2,4-bis(2,2-diethoxyethoxy)phenyl)prop-2-en-1-one). The emission wavelengths of the products are around 530 nm with high fluorescence intensity. To highlight the biological characteristics of these novel BODIPY fluorescents, we further demonstrated biological analysis studies on MTT and flow cytometry assays. The IC50 values of BODIPY 5 ranged from 79 ± 6.11 to 63 ± 5.67 µM and BODIPY 6 were found to be 86 ± 4.07 to 58 ± 10.51 µM in tested cell lines. Flow cytometry data analysis shows that the representative agent 6 and reference have similar rational apoptosis rates in first quadrant. Last but not least, 6 shows outstanding biological compatibility and cell imaging potential in live cell imaging and in vivo assay, not only is the fluorescence prominent enough, but also rapidly distributes. Thus, our study reports a mild synthesis strategy and full biological analysis on BODIPY fluorescents, and the subtle modulation of the physical and biological properties by pharmaceutical substituents makes these designed chalcone-BODIPY-based dyes hopeful to realize drug functional fluorescent dyes. Two new highly sensitive BODIPY fluorophores are synthesized based on the ligand ((Z)-2-chloro-1-(difluoroboranyl)-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)(phenyl)methyl)-1H-pyrrole), which connects with chalcone in (2E,2'E)-3,3'-(1,3/4-phenylene)bis(1-(2,4-bis(2,2-diethoxyethoxy)phenyl)prop-2-en-1-one). Multiple acetals were introduced and the physical and biological properties of BODIPYs are described with MTT assay and in vitro and in vivo imaging.


Assuntos
Acetais/química , Compostos de Boro/química , Chalconas/química , Corantes Fluorescentes/química , Acetais/síntese química , Animais , Apoptose , Compostos de Boro/síntese química , Chalconas/síntese química , Citometria de Fluxo , Corantes Fluorescentes/síntese química , Células HCT116 , Células HeLa , Humanos , Camundongos , Imagem Óptica
6.
Chem Asian J ; 16(7): 850-855, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33655662

RESUMO

Hydrogen sulfide (H2 S) is recognized as an endogenous gaseous signaling agent in many biological activities. Lysosomes are the main metabolic site and play a pivotal role in cells. Herein, we designed and synthesized two new fluorescent probes BDP-DNBS and BDP-DNP with a BODIPY core to distinguish H2 S. The sensing mechanism is based on the inhibition-recovery of the photo-induced electron transfer (PET) process. Through comparing the responsive behaviors of the two probes toward H2 S, BDP-DNBS showed a fast response time (60 s), low limit of detection (LOD, 51 nM), high sensitivity and selectivity. Moreover, the reaction mechanism was demonstrated by mass spectrometry and fluorescence off-on mechanism was proved by density functional theory (DFT). Significantly, confocal fluorescence imaging indicated that BDP-DNBS was successfully used to visualize H2 S in lysosomes in living HeLa cells.


Assuntos
Compostos de Boro/química , Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Lisossomos/metabolismo , Compostos de Boro/síntese química , Teoria da Densidade Funcional , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Sulfeto de Hidrogênio/química , Limite de Detecção , Microscopia Confocal , Microscopia de Fluorescência , Modelos Químicos
7.
Molecules ; 26(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672731

RESUMO

Despite significant interest, the chiroptical properties of subporphyrins have rarely been investigated because chiral subporphyrins are elusive. Here, inherently chiral subporphyrins are elaborated by forming a fused pyran ring at the periphery of an A2B-type meso-aryl-substituted subporphyrin. Their circular dichroism (CD) properties are largely affected by the peripheral substituents and the dihedral angles between the meso-aryl substituents and the subporphyrin core: the ß-perbromo subporphyrin with an orthogonal arrangement of the meso-phenyl substituents to the subporphyrin core exhibits weak CD signals corresponding to the Q bands, whereas the unsubstituted species with smaller dihedral angles shows relatively intense CD signals. A detailed structure-property relationship of these chiral subporphyrins was elucidated by time-dependent (TD) DFT calculations. This study reveals that the CD properties of chiral subporphyrins can be controlled by peripheral substitution and meso-aryl substituents.


Assuntos
Compostos de Boro/química , Porfirinas/química , Compostos de Boro/síntese química , Dicroísmo Circular , Teoria da Densidade Funcional , Conformação Molecular , Estereoisomerismo
8.
Org Biomol Chem ; 19(10): 2203-2212, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33496698

RESUMO

Here were report the combination of biocompatible click chemistry of ω-azidosphinganine with fluorescence microscopy and mass spectrometry as a powerful tool to elaborate the sphingolipid metabolism. The azide probe was efficiently synthesized over 13 steps starting from l-serine in an overall yield of 20% and was used for live-cell fluorescence imaging of the endoplasmic reticulum in living cells by bioorthogonal click reaction with a DBCO-labeled fluorophore revealing that the incorporated analogue is mainly localized in the endoplasmic membrane like the endogenous species. A LC-MS(/MS)-based microsomal in vitro assay confirmed that ω-azidosphinganine mimics the natural species enabling the identification and analysis of metabolic breakdown products of sphinganine as a key starting intermediate in the complex sphingolipid biosynthetic pathways. Furthermore, the sphinganine-fluorophore conjugate after click reaction was enzymatically tolerated to form its dihydroceramide and ceramide metabolites. Thus, ω-azidosphinganine represents a useful biofunctional tool for metabolic investigations both by in vivo fluorescence imaging of the sphingolipid subcellular localization in the ER and by in vitro high-resolution mass spectrometry analysis. This should reveal novel insights of the molecular mechanisms sphingolipids and their processing enzymes have e.g. in infection.


Assuntos
Azidas/metabolismo , Esfingolipídeos/análise , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Animais , Azidas/síntese química , Compostos de Boro/síntese química , Compostos de Boro/metabolismo , Linhagem Celular Tumoral , Chlorocebus aethiops , Química Click , Retículo Endoplasmático/metabolismo , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Humanos , Microscopia Confocal , Microscopia de Fluorescência , Esfingolipídeos/biossíntese
9.
Eur J Med Chem ; 213: 113171, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33482600

RESUMO

In this work, a series of structurally novel benzoxaborole derivatives were designed, synthesized and biologically evaluated as PDE4 inhibitors for battling atopic dermatitis (AD). Among them, the majority exhibited superior PDE4B inhibitory activities to that of the lead compound Crisaborole, an approved PDE4 inhibitor. In particular, 72, the most potent PDE4B inhibitor throughout this series, displayed 136-fold improved enzymatic activity (IC50 = 0.42 nM) as compared to Crisaborole (IC50 = 57.20 nM), along with favorable isoform specificity. In the phorbol ester (PMA)-induced mouse ear oedema model, 72 exerted remarkably greater efficacy than Crisaborole at the same dosage (P < 0.05). Moreover, the ointment of 72 exerted dramatically enhanced therapeutic potency than the ointment of Crisaborole (P < 0.05) in the calcipotriol-induced mouse AD model. In addition to the potent in vitro and in vivo activity, 72 displayed favorable safety in the repeated oral dose toxicity study and did not exhibit phototoxicity. With the above attractive biological performance, 72 is worthy of further functional investigation as a novel anti-AD therapeutic agent.


Assuntos
Compostos de Boro/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Fármacos , Inibidores da Fosfodiesterase 4/farmacologia , Animais , Compostos de Boro/síntese química , Compostos de Boro/química , Calcitriol/análogos & derivados , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Feminino , Cobaias , Masculino , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol
10.
ACS Appl Mater Interfaces ; 12(42): 47208-47219, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33035047

RESUMO

Conjugated molecules with coplanar strong donor and acceptor (D-A) units have been widely used in the design of near-infrared (NIR) photothermal agents to increase an absorption band through intramolecular charge transfer and to control intramolecular motions in aggregated states. However, such conjugated D-A systems have strong dipolar moments and intermolecular interactions, which may inhibit other channels of photothermal conversion and are often susceptible to nucleophiles, especially in the presence of light irradiation. Now, we report a molecular guideline to develop novel NIR organic photothermal nanoagents based on conjugated boron dipyrromethene (BODIPY) oligomers. This oligomerization is helpful not only for their tunable NIR absorptions in the ground state with distinctly redshifted absorption maxima up to 1002 nm and high extinction coefficients but also for their highly efficient photothermal conversion because of the possible motion of the BODIPY motifs around the ethene linked group in the excited state. These oligomers were fabricated as ultra-photostable nanoagents for multiple imaging-guided phototherapies, which efficiently accumulated in tumors, and gave complete tumor ablation with NIR laser irradiation. This strategy of "ground-state conjugation, excited-state rotation" provides a novel guideline to develop advanced theranostic molecules with NIR absorption.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Nanomedicina Teranóstica , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Raios Infravermelhos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Estrutura Molecular , Nanopartículas/química , Imagem Óptica , Tamanho da Partícula , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Propriedades de Superfície
11.
Molecules ; 25(19)2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33023057

RESUMO

This study focuses on the behavior of a new fluorescent marker for labeling individual biomolecules and staining cell organelles developed on a meso-substituted BODIPY platform. Boron(III) complex with meso-4-methoxycarbonylpropylsubstituted 3,3',5,5'-tetramethyl-2,2'-dipyrromethene has been synthesized and identified via visible, UV-, NMR- and MS-spectra X-ray. The behavior of fluorophore in solutions has been studied with various experimental techniques. It has been found that luminophore exhibits a high quantum yield (almost ~100-75%) in the blue-green region (513-520 nm) and has high photostability. In addition, biological analysis indicates that the fluorophore exhibits a tendency to effectively penetrate into cell membranes. On the other hand, the proposed BODIPY can be used to study the significant differences among a large number of pathogens of mycotic infections, as well as to visualize structural changes in the plasma membrane, which is necessary for the clearance of mammalian cells undergoing apoptotic cell death.


Assuntos
Boro/química , Diagnóstico por Imagem , Porfobilinogênio/análogos & derivados , Compostos de Boro/síntese química , Compostos de Boro/química , Candida albicans/citologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Doxorrubicina/farmacologia , Elétrons , Fusarium/citologia , Humanos , Porfobilinogênio/química , Solventes/química , Espectrometria de Fluorescência , Frações Subcelulares/metabolismo , Raios Ultravioleta
12.
ACS Chem Biol ; 15(11): 2996-3003, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33108866

RESUMO

Fluorescent nucleoside triphosphates are powerful probes of DNA synthesis, but their potential use in living animals has been previously underexplored. Here, we report the synthesis and characterization of 7-deaza-(1,2,3-triazole)-2'-deoxyadenosine-5'-triphosphate (dATP) derivatives of tetramethyl rhodamine ("TAMRA-dATP"), cyanine ("Cy3-dATP"), and boron-dipyrromethene ("BODIPY-dATP"). Upon microinjection into live zebrafish embryos, all three compounds were incorporated into the DNA of dividing cells; however, their impact on embryonic toxicity was highly variable, depending on the exact structure of the dye. TAMRA-EdATP exhibited superior characteristics in terms of its high brightness, low toxicity, and rapid incorporation and depletion kinetics in both a vertebrate (zebrafish) and a nematode (Caenorhabditis elegans). TAMRA-EdATP allows for unprecedented, real-time visualization of DNA replication and chromosome segregation in vivo.


Assuntos
Replicação do DNA , DNA/análise , Nucleotídeos de Desoxiadenina/química , Corantes Fluorescentes/química , Animais , Compostos de Boro/síntese química , Compostos de Boro/química , Caenorhabditis elegans/ultraestrutura , Carbocianinas/síntese química , Carbocianinas/química , Nucleotídeos de Desoxiadenina/síntese química , Corantes Fluorescentes/síntese química , Imagem Óptica/métodos , Rodaminas/síntese química , Rodaminas/química , Peixe-Zebra/embriologia
13.
Bioorg Med Chem ; 28(21): 115737, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065434

RESUMO

A new class of compounds based on the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene core, known as BODIPYs, has attracted significant attention as photosensitizers suitable for application in photodynamic therapy (PDT), which is a minimally invasive procedure to treat cancer. In PDT the combination of a photosensitizer (PS), light, and oxygen leads to a series of photochemical reactions generating reactive oxygen species (ROS) exerting cytotoxic action on tumor cells. Here we present the synthesis and the study of the in vitro photodynamic effects of two BODIPYs which differ in the structure of the substituent placed on the meso (or 8) position of the dipyrrolylmethenic nucleus. The two compounds were tested on three human cancer cell lines of different origin and degree of malignancy. Our results indicate that the BODIPYs are very effective in reducing the growth/viability of HCT116, SKOV3 and MCF7 cells when irradiated with a green LED source, whereas they are practically devoid of activity in the dark. Phototoxicity occurs mainly through apoptotic cell death, however necrotic cell death also seems to play a role. Furthermore, singlet oxygen generation and induction of the increase of reactive oxygen species also appear to be involved in the photodynamic effect of the BODIPYs. Finally, it is worth noting that the two BODIPYs are also able to exert anti-migratory activity.


Assuntos
Compostos de Boro/química , Fármacos Fotossensibilizantes/síntese química , Apoptose/efeitos dos fármacos , Compostos de Boro/síntese química , Compostos de Boro/metabolismo , Compostos de Boro/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Humanos , Luz , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Oxigênio Singlete/metabolismo
14.
Chem Soc Rev ; 49(21): 7533-7567, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-32996497

RESUMO

Boron-dipyrromethene (BODIPY) belongs to a family of organoboron compounds, commercialized as fluorescent dyes by Invitrogen™. As BODIPY derivatives, Aza-boron-dipyrromethene (Aza-BODIPY) dyes display superior spectral performances, such as red-shifted spectra and high molar extinction coefficients, and are considered to be extremely attractive organic materials for various bioapplications. Therefore, scientists from different disciplinary backgrounds would benefit from a review that provides a timely summary and outlook regarding Aza-BODIPY dyes. In this review, we report on the latest advances of Aza-BODIPY dyes, along with the empirical design guidelines and photophysical property manipulation of these dyes. In addition, we will discuss the biological applications of Aza-BODIPY dyes in probing various biological activities, as well as in fluorescence bioimaging/detection, newly-emerging photoacoustic bioimaging/detection, and phototherapy together with future challenges and implications in this field. We aim at providing an insightful design guideline and a clear overview of Aza-BODIPY dyes, which might entice new ideas and directions.


Assuntos
Compostos Aza/química , Compostos de Boro/química , Corantes Fluorescentes/química , Imagem Óptica , Técnicas Fotoacústicas , Compostos de Boro/síntese química , Corantes Fluorescentes/síntese química
15.
ACS Appl Mater Interfaces ; 12(40): 44523-44533, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-32910635

RESUMO

It is highly desired to explore ideal phototherapeutic nanoplatforms, especially containing satisfactory phototherapeutic agents (PTAs), for potential cancer therapies. Herein, we proposed an effective strategy for designing a highly efficient PTA through inhibiting radiative transition (IRT). Specifically, we developed an ultralow radiative BODIPY derivative (TPA-IBDP) by simply conjugating two triphenylamine units to iodine-substituted BODIPY, which could simultaneously facilitate the nonradiative decay channels of singlet-to-triplet intersystem crossing and intramolecular charge transfer. In comparison to the normal BODIPY compound, TPA-IBDP exhibited an outstanding singlet oxygen yield (31.8-fold) and a higher photothermal conversion efficiency (PCE; over 3-fold), respectively, benefiting from the extended π-conjugated donor-to-accepter (D-A) structure and the heavy atom effect. For tumor phototherapy using TPA-IBDP, TPA-IBDP was conjugated with a H2O2-responsive amphiphilic copolymer POEGMA10-b-[PBMA5-co-(PS-N3)2] to construct a multifunctional phototherapeutic BODIPY-based nanoplatform (PB). PB produced abundant singlet oxygen (1O2) and heat along with negligible fluorescence emission under near-infrared laser irradiation. Additionally, PB could generate a GSH-depletion scavenger (quinone methide, QM) after reacting with the abundant intracellular H2O2 in tumor for the cooperative enhancement of IRT-mediated phototherapy. We envision that this highly efficient multifunctional phototherapeutic nanoplatform cooperated by GSH-depletion could be a valuable paradigm for tumor treatments.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Neoplasias da Mama/tratamento farmacológico , Nanopartículas/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Polímeros/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Feminino , Camundongos , Tamanho da Partícula , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Propriedades de Superfície
16.
J Am Chem Soc ; 142(42): 18213-18222, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-32962336

RESUMO

We report the incorporation of large substituents based on heavy main-group elements that are atypical in ligand architectures to enhance dispersion interactions and, thereby, enhance enantioselectivity. Specifically, we prepared the chiral biaryl bisphosphine ligand (TMG-SYNPHOS) containing 3,5-bis(trimethylgermanyl)phenyl groups on phosphorus and applied this ligand to the challenging problem of enantioselective hydrofunctionalization reactions of 1,1-disubtituted alkenes. Indeed, TMG-SYNPHOS forms a copper complex that catalyzes hydroboration of 1,1-disubtituted alkenes with high levels of enantioselectivity, even when the two substituents are both primary alkyl groups. In addition, copper catalysts bearing ligands possessing germanyl groups were much more active for hydroboration than one derived from DTBM-SEGPHOS, a ligand containing 3,5-di-tert-butyl groups and widely used for copper-catalyzed hydrofunctionalization. This observation led to the identification of DTMGM-SEGPHOS, a bisphosphine ligand bearing 3,5-bis(trimethylgermanyl)-4-methoxyphenyl groups as the substituents on the phosphorus, as a new ligand that forms a highly active catalyst for hydroboration of unactivated 1,2-disubstituted alkenes, a class of substrates that has not readily undergone copper-catalyzed hydroboration previously. Computational studies revealed that the enantioselectivity and catalytic efficiency of the germanyl-substituted ligands is higher than that of the silyl and tert-butyl-substituted analogues because of attractive dispersion interactions between the bulky trimethylgermanyl groups on the ancillary ligand and the alkene substrate and that Pauli repulsive interactions tended to decrease enantioselectivity.


Assuntos
Alcenos/química , Compostos de Boro/síntese química , Cobre/química , Compostos Organometálicos/química , Fosfinas/química , Compostos de Boro/química , Catálise , Ligantes , Estrutura Molecular , Fosfinas/síntese química
17.
ACS Appl Mater Interfaces ; 12(37): 41071-41078, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32806896

RESUMO

As an important noninvasive tumor treatment method, phototherapy has drawn extensive research interest. However, the requirements of separate excitation wavelengths, high degree of electron-hole recombination, and low reactive oxygen species (ROS) production capability are still the major barriers. This work reports the construction of a novel nanoplatform: design and synthesis of an aza-BODIPY (AB) probe-decorated mesoporous black titanium dioxide (TiO2) (MT) nanoparticles (NPs) for enhanced photodynamic therapy and photothermal therapy under single-wavelength near-infrared (NIR) laser irradiation for the first time. AB probe-decorated MT NPs (abbreviated as MTAB) were synthesized through the Al reduction of mesoporous anatase TiO2 NPs and subsequent adsorption of the AB probe. The mesoporous structure of MT ensured AB loading capacity and avoided the complicated modification and synthesis processes. Heterogeneous MTAB, which possessed staggered energy levels, were assessed for their capability for effective separation of photogenerated electrons and holes for the first time. Upon NIR laser light irradiation, MTAB exhibited sufficient ROS generation, resulting in distinct tumor cell killing and tumor tissue elimination. This unique heterogeneous nanoplatform with staggered energy levels provides a new strategy to enhance ROS generation and improve the therapeutic efficacy.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Neoplasias da Mama/tratamento farmacológico , Nanopartículas/química , Fototerapia , Titânio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Raios Infravermelhos , Camundongos , Tamanho da Partícula , Porosidade , Espécies Reativas de Oxigênio/metabolismo , Propriedades de Superfície , Titânio/química
18.
Molecules ; 25(16)2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32823576

RESUMO

Two near-infrared (NIR) absorbing di(thien-2-nyl)-di(dimethylanilino)azaBODIPY dyes 2a and 2b were synthesized and characterized that differ depending on whether the dimethylaniline substituents are introduced at the 3,5- or 1,7-positions of the azaBODIPY core. The main spectral bands lie at 824 and 790 nm, respectively, in CH2Cl2. The effect of substituent position on the photophysical and pH sensing properties was analyzed through a comparison of the optical properties with the results of time-dependent density functional theory (TD-DFT) calculations. Protonation of the dimethylamino nitrogen atoms eliminates the intramolecular charge transfer properties of these compounds, and this results in a marked blue-shift of the main absorption bands to 696 and 730 nm, respectively, in CH2Cl2, and a fluorescence "turn-on" effect in the NIR region. The pH dependence studies reveal that the pKa values of the non-protonated 2a and 2b molecules are ca. 6.9 (±0.05) and 7.3 (±0.05), respectively, while that of the monoprotonated species for both dyes is ca. 1.4 (±0.05) making them potentially suitable for use as colorimetric pH indicators under highly acidic conditions.


Assuntos
Absorção Fisico-Química , Compostos de Boro/química , Corantes/química , Raios Infravermelhos , Compostos de Boro/síntese química , Teoria da Densidade Funcional , Transporte de Elétrons , Concentração de Íons de Hidrogênio
19.
J Med Chem ; 63(17): 9950-9964, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787080

RESUMO

Photodynamic therapy (PDT) as a rising platform of the cancer treatment method is receiving increased attention. Through systematic evaluation of halogen substitution on aza-4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPY), we have found that monoiodo-derived aza-BODIPYs provided greater efficacy than other halogenated aza-BODIPY PSs. 4 and 15 as monoiodinated aza-BODIPY dyes containing p-methoxyphenyl moiety were identified to be potent NIR aza-BODIPY-type PSs with IC50 values against HeLa cells at a light dose of 54 J/cm2 as low as 76 and 81 nM, respectively. 4 possessed superior phototoxicity, low dark toxicity, and good thermal/photostability and distributed majorly in mitochondria in cells. Apoptosis was verified to be the main cell death pathway, and in vitro reactive oxygen species generation was demonstrated. In vivo whole-body fluorescence imaging and ex vivo organ distribution studies suggested that 4 afforded an excellent PDT effect with a low drug dose under single-time light irradiation and revealed advantages over known PSs of ADPM06 and Ce6.


Assuntos
Antineoplásicos/uso terapêutico , Compostos de Boro/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Compostos de Boro/síntese química , Compostos de Boro/efeitos da radiação , Linhagem Celular Tumoral , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/uso terapêutico , Humanos , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Int J Mol Sci ; 21(16)2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32764353

RESUMO

Calcium ions regulate a wide array of physiological functions including cell differentiation, proliferation, muscle contraction, neurotransmission, and fertilization. The endoplasmic reticulum (ER) is the major intracellular Ca2+ store and cellular events that induce ER store depletion (e.g., activation of inositol 1,4,5-triphosphate (IP3) receptors) trigger a refilling process known as store-operated calcium entry (SOCE). It requires the intricate interaction between the Ca2+ sensing stromal interaction molecules (STIM) located in the ER membrane and the channel forming Orai proteins in the plasma membrane (PM). The resulting active STIM/Orai complexes form highly selective Ca2+ channels that facilitate a measurable Ca2+ influx into the cytosol followed by successive refilling of the ER by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). STIM and Orai have attracted significant therapeutic interest, as enhanced SOCE has been associated with several cancers, and mutations in STIM and Orai have been linked to immunodeficiency, autoimmune, and muscular diseases. 2-Aminoethyl diphenylborinate (2-APB) is a known modulator and depending on its concentration can inhibit or enhance SOCE. We have synthesized several novel derivatives of 2-APB, introducing halogen and other small substituents systematically on each position of one of the phenyl rings. Using a fluorometric imaging plate reader (FLIPR) Tetra-based calcium imaging assay we have studied how these structural changes of 2-APB affect the SOCE modulation activity at different compound concentrations in MDA-MB-231 breast cancer cells. We have discovered 2-APB derivatives that block SOCE at low concentrations, at which 2-APB usually enhances SOCE.


Assuntos
Compostos de Boro/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteínas de Neoplasias/genética , Proteína ORAI1/genética , Molécula 1 de Interação Estromal/genética , Moléculas de Interação Estromal/genética , Animais , Compostos de Boro/síntese química , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Complexos Multiproteicos/antagonistas & inibidores , Complexos Multiproteicos/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteína ORAI1/química , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Molécula 1 de Interação Estromal/antagonistas & inibidores , Moléculas de Interação Estromal/antagonistas & inibidores
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