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1.
Chem Biol Interact ; 330: 109236, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32866467

RESUMO

A series of novel pyrrolopyrimidine urea derivatives were synthesized and evaluated for their anticancer activity against colon cancer cell lines. Compounds showed the remarkable cytotoxic activity on HCT-116 wt cell line. The most potent compound 4c (IC50 = 0.14 µM) induced apoptosis in HCT-116 wt and HCT-116 p53-/- cell lines. Otherwise, treatment of HCT-116 BAX-/-BAK-/- cells with compound 4c didn't lead to activation of apoptosis, suggesting that compound 4c induces apoptotic cell death by activating BAX/BAK-dependent pathway. Moreover, while the compound 4c increase the activation of caspase-3 and caspase-9 levels in HCT-116 wt and HCT-116 p53-/- cells, caspase-3 or caspase-9 activation was not observed in HCT-116 BAX-/-BAK-/- cells. In addition, compound 4c induced mitochondrial apoptosis in cells grown as oncospheroids, which better mimic the in vivo milieu of tumors. 4c treatment also activated JNK along with inhibition of prosurvival kinases such as Akt and ERK 1/2 in HCT-116 wt and HCT-116 p53 -/- cells as well as in HCT-116 BAX-/-BAK-/- cells. Notably, our results indicated that compound 4c induced mitochondrial apoptosis through activation p53-independent apoptotic signaling pathways.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Pirimidinas/farmacologia , Pirróis/farmacologia , Proteína Supressora de Tumor p53/fisiologia , Caspase 3/genética , Caspase 9/genética , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Técnicas de Inativação de Genes , Células HCT116 , Humanos , Mitocôndrias/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Proteína Supressora de Tumor p53/genética , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/genética
2.
Int J Nanomedicine ; 15: 2605-2615, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368043

RESUMO

Objective: This paper introduces a simple one-step and ultra-fast method for synthesis of highly photothermally active polypyrrole-coated gold nanoparticles. The synthesis process is so simple that the reaction is very fast without the need for any additives or complicated steps. Methodology: Polypyrrole-coated gold nanoparticles (AuPpy NPs) were synthesized by reacting chloroauric acid (HAuCl4) with pyrrole (monomer) in aqueous medium at room temperature. These nanoparticles were characterized by UV-visible-NIR spectrometry, transmission electron microscopy (TEM), AC conductivity, zeta sizer and were evaluated for dark cytotoxicity and photocytotoxicity using human hepatocellular carcinoma (HepG2) cell line as a model for cancer cells. Results: The synthesized AuPpy NPs showed a peak characteristic for gold nanoparticles (530-600 nm, molar ratio dependent) and a wide absorption band along the visible-NIR region with intensity about triple or even quadruple that of polypyrrole synthesized by the conventional FeCl3 method at the same concentration and under the same conditions. TEM imaging showed that the synthesized AuPpy NPs were composed of spherical or semi-spherical gold core(s) of about 4-10 nm coated with distinct layer(s) of polypyrrole seen either loosely or in clusters. Mean sizes of the synthesized nanoparticles range between ~25 and 220 nm (molar ratio dependent). Zeta potentials of the AuPpy NPs preparations indicate their good colloidal stability. AC conductivity values of AuPpy NPs highly surpass that of Ppy prepared by the conventional FeCl3 method. AuPpy NPs were non-toxic even at high concentrations (up to 1000 µM pyrrole monomer equivalent) under dark conditions. Unlikely, light activated the photothermal activity of AuPpy NPs in a dose-dependent manner. Conclusion: This method simply and successfully synthesized AuPpy NPs nanoparticles that represent a safe alternative photothermally active multifunctional tool instead of highly toxic and non-biodegradable gold nanorods.


Assuntos
Materiais Revestidos Biocompatíveis/química , Ouro/química , Luz , Nanopartículas Metálicas/química , Polímeros/química , Pirróis/química , Temperatura , Morte Celular , Cloretos/química , Condutividade Elétrica , Compostos de Ouro/química , Células Hep G2 , Humanos , Nanopartículas Metálicas/ultraestrutura , Tamanho da Partícula , Polímeros/síntese química , Pirróis/síntese química , Espectrofotometria Ultravioleta , Eletricidade Estática
3.
J Med Chem ; 63(4): 1724-1749, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32031803

RESUMO

We previously reported a milestone in the optimization of NBD-11021, an HIV-1 gp120 antagonist, by developing a new and novel analogue, NBD-14189 (Ref1), which showed antiviral activity against HIV-1HXB2, with a half maximal inhibitory concentration of 89 nM. However, cytotoxicity remained high, and the absorption, distribution, metabolism, and excretion (ADME) data showed relatively poor aqueous solubility. To optimize these properties, we replaced the phenyl ring in the compound with a pyridine ring and synthesized a set of 48 novel compounds. One of the new analogues, NBD-14270 (8), showed a marked improvement in cytotoxicity, with 3-fold and 58-fold improvements in selectivity index value compared with that of Ref1 and NBD-11021, respectively. Furthermore, the in vitro ADME data clearly showed improvements in aqueous solubility and other properties compared with those for Ref1. The data for 8 indicated that the pyridine scaffold is a good bioisostere for phenyl, allowing the further optimization of this molecule.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Piridinas/farmacologia , Pirróis/farmacologia , Tiazóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Células CACO-2 , Células HEK293 , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/síntese química , Piridinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética
4.
Alkaloids Chem Biol ; 83: 1-112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32098648

RESUMO

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


Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/isolamento & purificação , Pirróis/farmacologia , Inibidores da Topoisomerase I/farmacologia , Alcaloides/síntese química , Alcaloides/química , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Pirróis/síntese química , Pirróis/química , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/isolamento & purificação
6.
Molecules ; 25(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936442

RESUMO

A novel generation of indole-2,3-quinodimethanes via the deamination of 1,2,3,4-tetrahydropyrrolo[s3,4-b]indoles is reported.


Assuntos
Indóis/química , Pirróis/química , Desaminação , Indóis/síntese química , Nitritos/química , Pirróis/síntese química
7.
Eur J Med Chem ; 188: 112021, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901743

RESUMO

A series of novel sulfonamide derivatives bearing pyrrole and pyrrolopyrimidine scaffolds were synthesized and screened as carbonic anhydrase inhibitors. The inhibition activity of the synthesized compounds was evaluated against the cytosolic human carbonic anhydrase isoforms I and II and the transmembranal isoforms IX and XII. Several candidates showed potent inhibitory activity against IX and XII isoforms. Furthermore, ex vivo screening of cytotoxic selectivity and activity of the most potent derivatives were carried out against normal cells (WI38) and cervical cancer cell line (HeLa) under normal and hypoxic conditions using acetazolamide as reference drug. Compound 11b potency was nearly three folds higher in hypoxic than normoxic condition whereas that of compound 11f was nearly four folds higher in hypoxic vs. normoxic HeLa cells. All the screened derivatives exhibited less potency on normal cells (WI38). Molecular docking was carried out to discover the possible binding mode of compounds within the active site of isoform CA IX.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/toxicidade , Domínio Catalítico , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/toxicidade , Pirróis/síntese química , Pirróis/toxicidade , Sulfonamidas/síntese química , Sulfonamidas/toxicidade
8.
Eur J Med Chem ; 188: 111988, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901746

RESUMO

In connection with our continued research to generate new aza-fused heteroaromatic chemical scaffolds, we developed a highly atom-economical three-component route to novel 3,4-dihydropyrrolo[1,2-a]pyrazine ring skeleton multi-functionalized on the pyrazine unit. This [4+1+1] annulation approach led us to gain access to a new N-fused bicyclic chemical space having two distinctive functional groups (heteroaryl and aroyl) in a trans manner. Investigation of anticancer activity of the synthesized compounds and their derivatives revealed that (3R*,4S*)-3-(4-bromophenyl)-4-(4-fluorobenzoyl)-2-(2-oxo-2-phenylethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2-ium bromide (3h) has potent anticancer activity. 3h significantly inhibited cell viability in prostate cancer cells (PC-3) and breast cancer cells (MCF-7) with IC50 value of 1.18 ± 0.05 µM and 1.95 ± 0.04 µM, respectively. In addition, 3h strongly reduced cell migration in a dose dependent manner, and induced apoptosis via caspase-3 activation and cleavage of PARP in PC-3 and MCF-7 cells. Our results in this study imply that 3h can be a potential anticancer agent against prostate cancer and breast cancer.


Assuntos
Antineoplásicos/farmacologia , Pirazinas/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Poli(ADP-Ribose) Polimerases/metabolismo , Pirazinas/síntese química , Pirazinas/química , Pirróis/síntese química , Pirróis/química
9.
Molecules ; 25(2)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936802

RESUMO

This manuscript reports the improved synthesis of the α,α,α,α isomer of tetra-p-iodophenyl tetra-methyl calix[4]pyrrole and the X-ray characterization of two solvate polymorphs. In the solid state, the calix[4]pyrrole receptor adopts the cone conformation, including one acetonitrile molecule in its aromatic cavity by establishing four convergent hydrogen bonds between its nitrogen atom and the four pyrrole NHs of the former. The inclusion complexes pack into rods, displaying a unidirectional orientation. In turn, the rods form flat 2D-layers by alternating the orientation of their p-iodo substituents. The 2D layers stack on top of another, resulting in a head-to-head and tail-to-tail orientation of the complexes or their exclusive arrangement in a head-to-tail geometry. The dissimilar stacking of the layers yields two solvate polymorphs that are simultaneously present in the structures of the single crystals. The ratio of the two polymorph phases is regulated by the amount of acetonitrile added to the chloroform solutions from which the crystals grow. Halogen bonding interactions are highly relevant in the crystal lattices of the two polymorphs. We analyzed and characterized these interactions by means of density functional theory (DFT) calculations and several computational tools. Remarkably, single crystals of a solvate containing two acetonitrile molecules per calix[4]pyrrole were obtained from pure acetonitrile solution.


Assuntos
Modelos Moleculares , Pirróis/química , Pirróis/síntese química , Cristalografia por Raios X , Isomerismo , Estrutura Molecular
10.
Mater Sci Eng C Mater Biol Appl ; 107: 110325, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761222

RESUMO

Synthesis of nanomaterials having uniform shape and size is a challenging task. Properties exhibited by such substrates would be compatible and homogeneous compared to the average properties displayed by those substrates with heterogeneous size. Herein, we report the synthesis of polypyrrole nanorods (PPy-NRs) of almost uniform size via oxidative chemical polymerization of pyrrole within anodized aluminum oxide nanopores followed by sacrificial removal of the template. Field emission scanning electron microscopy (FE-SEM), fourier transformed infra-red (FT-IR) spectra, X-ray diffraction (XRD), and ultra-violet-visible-near infra-red (UV-Vis-NIR) spectra of the substrate were used to analyze the physicochemical properties of as-synthesized PPy-NRs. PPy-NRs treated MC3T3-E1 and PC12 cells exhibited good biocompatibility in CCK-8 and live/dead assays. The assay showed more cell viability on PC12 cell lines. Electrical stimulation through PPy-NRs treated PC12 cells accelerated neuronal differentiation compared to those without electrical stimulation during in vitro cell culture.


Assuntos
Nanoporos , Nanotubos/química , Neurônios/efeitos dos fármacos , Polímeros/síntese química , Polímeros/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Óxido de Alumínio/isolamento & purificação , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular , Estimulação Elétrica , Camundongos , Microscopia Eletrônica de Varredura , Neurônios/fisiologia , Osteoblastos/efeitos dos fármacos , Células PC12 , Polimerização , Ratos , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
11.
Biomed Res Int ; 2019: 2514524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815127

RESUMO

A- and D-ring-modified luotonin-inspired heterocycles have been synthesized and were evaluated for their activity against the viability of four cancer cell lines in vitro, namely, MCF7, HCT116, JURKAT, and NCI-H460. The analysis of results indicated that two of the synthesized derivatives displayed good inhibition against the growth of the human colon cancer HCT116 cell line, with potencies lower than but in the same order of magnitude as camptothecin (CPT). These two luotonin analogues also showed an activity similar to that of the highly potent alkaloid CPT as inhibitors of topoisomerase I and also inhibited topoisomerase II. These results show that complete planarity is not a strict requirement for topoisomerase inhibition by luotonin-related compounds, paving the way to the design of analogues with improved solubility.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/efeitos dos fármacos , DNA Topoisomerases Tipo I/efeitos dos fármacos , Proteínas de Ligação a Poli-ADP-Ribose/efeitos dos fármacos , Pirróis/síntese química , Pirróis/farmacologia , Quinonas/síntese química , Quinonas/farmacologia , Inibidores da Topoisomerase/farmacologia , Alcaloides/farmacologia , Camptotecina/análogos & derivados , Camptotecina/síntese química , Linhagem Celular Tumoral/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Solubilidade , Relação Estrutura-Atividade
12.
Molecules ; 24(23)2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31795117

RESUMO

This review presents the most recent developments on the synthesis of dipyrromethanes, covering classical synthetic strategies, using acid catalyzed condensation of pyrroles and aldehydes or ketones, and recent breakthroughs which allow the synthesis of these type of heterocycles with new substitution patterns.


Assuntos
Pirróis/síntese química , Aldeídos/química , Catálise , Técnicas de Química Sintética , Ácido Clorídrico , Índio/química , Estrutura Molecular , Pirróis/química
13.
Molecules ; 24(20)2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31635419

RESUMO

We report here the synthesis and optical spectral properties of several new pyrrolodiazine derivatives. The luminescent heterocycles were synthesized by 1,3-dipolar cycloaddition reactions between N-alkylated pyridazine and methylpropiolate or dimethyl acetylenedicarboxylate (DMAD). The pyrrolopyridazine derivatives are blue emitters with moderate quantum yields (around 25%) in the case of pyrrolopyridazines and negligible yet measurable emission for pyrrolophthalazines. In a subsequent step towards including the pyrrolodiazine moiety, given its spectral properties in various macromolecular frameworks such as biological molecules, a subset of the synthetized compounds has been subjected to α-bromination. A selective and efficient way for α-bromination in heterogeneous catalysis of pyrrolodiazine derivatives under microwave (MW) irradiation is presented. We report substantially higher yields under MW irradiation, whereas the solvent amounts required are at least five-fold less compared to classical heating.


Assuntos
Ftalazinas/química , Piridazinas/síntese química , Pirróis/síntese química , Reação de Cicloadição , Fluorescência , Micro-Ondas , Estrutura Molecular , Piridazinas/química , Pirróis/química
14.
Molecules ; 24(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652581

RESUMO

Herein we report a significant, valuable extension of a recently implemented pyrrole benzannulation methodology that, employing versatile nitrodienes from our lab as useful C4 building blocks, led to indole derivatives characterized by unusual patterns of substitution. The 6-nitro-7-arylindoles resulting from suitably derivatized, non-symmetric dienes are of foreseeable synthetic interest in search for new polyheterocyclic systems. As an example, pyrrolocarbazoles with a rarely reported ring fusion were synthesized with the classical Cadogan protocol. Furthermore, the proven easy reducibility of the nitro group to amine will surely open the way to further interesting elaborations.


Assuntos
Carbazóis/química , Indóis/química , Pirróis/química , Carbazóis/síntese química , Indóis/síntese química , Estrutura Molecular , Pirróis/síntese química
15.
Chemistry ; 25(69): 15779-15785, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31523878

RESUMO

A series of fluoroalkylated cyclic λ3 -iodanes and their hydrochloride salts was prepared and used in a combination with sodium ascorbate in buffer or aqueous methanol mixtures for radical fluoroalkylation of a range of substituted indoles, pyrroles, tryptophan or its derivatives, and Trp residues in peptides. As demonstrated on several peptides, the aromatic amino acid residues of Trp, Tyr, Phe, and His are targeted with high selectivity to Trp. The functionalization method is biocompatible, mild, rapid, and transition-metal-free. The proteins myoglobin, ubiquitin, and human carbonic anhydrase I were also successfully functionalized.


Assuntos
Aminoácidos Aromáticos/química , Indóis/química , Peptídeos/química , Proteínas/química , Pirróis/química , Alquilação , Aminoácidos Aromáticos/síntese química , Radicais Livres/síntese química , Radicais Livres/química , Halogenação , Humanos , Indóis/síntese química , Modelos Moleculares , Peptídeos/síntese química , Proteínas/síntese química , Pirróis/síntese química
16.
Chem Commun (Camb) ; 55(73): 10920-10923, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31441463

RESUMO

The development of new NIR-II fluorophores, particularly those with facile syntheses, high fluorescence quantum yields, and stable and tunable photophysical properties, is challenging. Herein, we report a new class of small molecular NIR-II fluorophores based on aza-dipyrromethene boron difluoride (aza-BODIPY) dyes. We demonstrate promising photophysical properties of these dyes, such as large Stokes shift, superior photostability, and good fluorescence brightness as nanoparticles in aqueous solution. Because of these properties and high resolution and deep penetration NIR-II imaging ability, the aza-BODIPY based dyes show great potential as NIR-II imaging agents.


Assuntos
Compostos de Boro/química , Corantes Fluorescentes/química , Imagem Óptica/métodos , Pirróis/química , Animais , Compostos de Boro/síntese química , Compostos de Boro/efeitos da radiação , Compostos de Boro/toxicidade , Linhagem Celular Tumoral , Teoria da Densidade Funcional , Desenho de Fármacos , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Raios Infravermelhos , Camundongos , Modelos Químicos , Nanopartículas/química , Poloxâmero/química , Pirróis/síntese química , Pirróis/efeitos da radiação , Pirróis/toxicidade
18.
Carbohydr Res ; 483: 107751, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374379

RESUMO

A 6-azido-2-tosylenolate, obtained from D-glucono-1,5-lactone in six steps, underwent an intramolecular cycloaddition-elimination pathway under mild conditions, yielding a chiral, substituted 5,6-dihydro-4H-pyrrolo[1,2-c]-1,2,3-triazole. The conditions were optimized to give exclusive formation of the triazole. The mechanism appears to involve intramolecular ring closure via a 1,3-dipolar azide-alkene cycloaddition to give a 1,2,3-triazoline, followed by elimination of p-toluenesulfonic acid, leading to aromatization. Triazole products, obtained by chemical modification, are expected to display activity as enzyme inhibitors. Furthermore, partially protected derivatives of the 2-hexenoate were prepared as useful synthetic intermediates.


Assuntos
Inibidores Enzimáticos/síntese química , Pirróis/síntese química , Triazóis/síntese química , Alcenos/química , Azidas/química , Reação de Cicloadição , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Pirróis/química , Pirróis/farmacologia , Triazóis/química , Triazóis/farmacologia
19.
Chemistry ; 25(58): 13354-13362, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31338861

RESUMO

New L-shaped fluorophores possessing five conjugated rings have been synthesized through a four-step procedure involving diketopyrrolopyrrole synthesis and its double N-alkylation, followed by trimethylsilyl bromide-mediated rearrangement to thieno[2,3-f]isoindole-5,8-dione and an intramolecular Friedel-Crafts reaction. In comparison with the parent isoindolediones and π-expanded diketopyrrolopyrroles, these new dyes show red-shifted absorption and emission (up to ≈630 nm). Their structural rigidity is responsible for both the observed small Stokes shifts and large fluorescence quantum yields. Tissue imaging studies revealed that these new dyes show advantageous features including minimal autofluorescence interference and pronounced solvent-sensitive emission. Interestingly, there is a fundamental difference between a dye possessing an amino group and its analog bearing an N-alkyl substituent. The former dye under two-photon excitation at 900 nm gives bright images whereas its N-alkylated counterpart does not. A new type of membrane localization has been discovered by an N-alkylated isoindoledione possessing a benzofuryl substituent. In spite of the fact that the fluorescence quantum yield of this dye in a range of solvents is rather low, it does stain cell membranes exclusively. This new mode of cellular staining opens the door towards further development of membrane staining dyes.


Assuntos
Corantes Fluorescentes/química , Isoindóis/química , Células A549 , Animais , Humanos , Cetonas/síntese química , Camundongos Endogâmicos BALB C , Imagem Óptica , Pirróis/síntese química , Compostos de Trimetilsilil/química
20.
Molecules ; 24(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340431

RESUMO

Pyrrolo[3,2-d]pyrimidines have been studied for many years as potential lead compounds for the development of antiproliferative agents. Much of the focus has been on modifications to the pyrimidine ring, with enzymatic recognition often modulated by C2 and C4 substituents. In contrast, this work focuses on the N5 of the pyrrole ring by means of a series of novel N5-substituted pyrrolo[3,2-d]pyrimidines. The compounds were screened against the NCI-60 Human Tumor Cell Line panel, and the results were analyzed using the COMPARE algorithm to elucidate potential mechanisms of action. COMPARE analysis returned strong correlation to known DNA alkylators and groove binders, corroborating the hypothesis that these pyrrolo[3,2-d]pyrimidines act as DNA or RNA alkylators. In addition, N5 substitution reduced the EC50 against CCRF-CEM leukemia cells by up to 7-fold, indicating that this position is of interest in the development of antiproliferative lead compounds based on the pyrrolo[3,2-d]pyrimidine scaffold.


Assuntos
Antineoplásicos/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
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