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1.
Chemistry ; 30(34): e202400644, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38619336

RESUMO

The 2,1,3-benzothiadiazole (BTD) unit is a prominent building block commonly used in various research areas such as optoelectronics and bioimaging. Despite its great versatility, the development of strategies to elaborate BTD has been largely neglected, including exploring its reactivity and understanding how regioselective functionalization can be used to tune the fluorescence emission. Previous focus has primarily been on C4- or C4,C7-substitutions. Here, a series of unsymmetrical mono - and disubstituted BTDs was synthesized and characterized for their photophysical properties. The reaction scope includes all six possible substituent patterns on the BTD benzoid ring (C4-, C5-, C4,C5-, C4,C6-, C4,C7- and C5,C6-substitution), which comprise arrangements that previously been synthetically challenging to access. By introducing a methoxy and/or a phenyl group we demonstrate that the emissive behavior of BTD derivatives strongly depends on the position of the substituent (s). We show that regioselective substitution on BTD can engender long-lived fluorescence and circumvent strong fluorescence quenching in polar protic solvents, which is a limitation of many previously described BTD derivatives.

2.
J Org Chem ; 89(9): 6138-6148, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38648018

RESUMO

Despite growing interest in 2,1,3-benzothiadiazole (BTD) as an integral component of many functional molecules, methods for the functionalization of its benzenoid ring have remained limited, and many even simply decorated BTDs have required de novo synthesis. We show that regioselective Ir-catalyzed C-H borylation allows access to versatile 5-boryl or 4,6-diboryl BTD building blocks, which undergo functionalization at the C4, C5, C6, and C7 positions. The optimization and regioselectivity of C-H borylation are discussed. A broad reaction scope is presented, encompassing ipso substitution at the C-B bond, the first examples of ortho-directed C-H functionalization of BTD, ring closing reactions to generate fused ring systems, as well as the generation and capture reactions of novel BTD-based heteroarynes. The regioselectivity of the latter is discussed with reference to the Aryne Distortion Model.

3.
Dalton Trans ; 53(12): 5658-5664, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38441110

RESUMO

A series of 2,1,3-benzothiadiazole-Au(I)-L complexes have been synthesised, structurally characterised and investigated for their photophysical properties. These are the first organometallic Au(I) complexes containing a C-Au bond on the highly electron-deficient benzothiadiazole unit. The complexes exhibit solution-phase phosphorescence at room temperature, assigned to the intrinsic triplet state of the benzothiadiazole unit that is efficently populated through its attachment to gold. Comparison with routinely reported Au(I) complexes, which include intervening alkenyl linkers, suggests that previous assignments of their phosphorescence as 1π → π*(CCR) might be incomplete. Our observations affirm that, in addition to the heavy atom effect, breaking symmetry in the involved aryl motif may be of importance in controlling the luminescence properties.

4.
Proc Natl Acad Sci U S A ; 121(7): e2310479121, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38335255

RESUMO

Metabolic reprogramming is critical during clear cell renal cell carcinoma (ccRCC) tumorigenesis, manifested by accumulation of lipid droplets (LDs), organelles that have emerged as new hallmarks of cancer. Yet, regulation of their biogenesis is still poorly understood. Here, we demonstrate that MYC inhibition in ccRCC cells lacking the von Hippel Lindau (VHL) gene leads to increased triglyceride content potentiating LD formation in a glutamine-dependent manner. Importantly, the concurrent inhibition of MYC signaling and glutamine metabolism prevented LD accumulation and reduced tumor burden in vivo. Furthermore, we identified the hypoxia-inducible lipid droplet-associated protein (HILPDA) as the key driver for induction of MYC-driven LD accumulation and demonstrated that conversely, proliferation, LD formation, and tumor growth are impaired upon its downregulation. Finally, analysis of ccRCC tissue as well as healthy renal control samples postulated HILPDA as a specific ccRCC biomarker. Together, these results provide an attractive approach for development of alternative therapeutic interventions for the treatment of this type of renal cancer.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Gotículas Lipídicas , Proteínas Proto-Oncogênicas c-myc , Humanos , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glutamina/metabolismo , Neoplasias Renais/patologia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Regulação para Cima , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
5.
Chemistry ; 29(51): e202300864, 2023 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-37332083

RESUMO

The study of a fluorescent indolin-3-one derivative is reported that, as opposed to its previously described congeners, selectively undergoes photoactivated ring-opening in apolar solvents. The excited state involved in this photoisomerization was partially deactivated by the formation of singlet oxygen. Cell studies revealed lipid droplet accumulation and efficient light-induced cytotoxicity.


Assuntos
Oxigênio Singlete , Solventes
6.
RSC Adv ; 12(23): 14544-14550, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35702197

RESUMO

In this work, a series of fluorescent 2,1,3-benzothiadiazole derivatives with various N-substituents in the 4-position was synthesized and photophysically characterized in various solvents. Three compounds emerged as excellent fluorescent probes for imaging lipid droplets in cancer cells. A correlation between their high lipophilicity and lipid droplet specificity could be found, with log P ≥ 4 being characteristic for lipid droplet accumulation.

7.
RSC Adv ; 11(39): 23960-23967, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35479010

RESUMO

We present an extensive photophysical study of a series of fluorescent indolylbenzothiadiazole derivatives and their ability to specifically image lipid droplets in astrocytes and glioblastoma cells. All compounds in the series displayed positive solvatochromism together with large Stokes shifts, and π-extended derivatives exhibited elevated brightness. It was shown that the fluorescence properties were highly tunable by varying the electronic character or size of the N-substituent on the indole motif. Three compounds proved capable as probes for detecting small quantities of lipid deposits in healthy and cancerous brain cells. In addition, all twelve compounds in the series were predicted to cross the blood-brain barrier, which raises the prospect for future in vivo studies for exploring the role of lipid droplets in the central nervous system.

8.
Chem Sci ; 8(8): 5636-5643, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28989601

RESUMO

Alzheimer's disease (AD) is a multifactorial disease that is characterized by the formation of intracellular neurofibrillary tangles and extracellular amyloid-ß (Aß) plaque deposits. Increased oxidative stress, metal ion dysregulation, and the formation of toxic Aß peptide oligomers are all considered to contribute to the etiology of AD. In this work we have developed a series of ligands that are multi-target-directed in order to address several disease properties. 2-(1-(3-Hydroxypropyl)-1H-1,2,3-triazol-4-yl)phenol (POH), 2-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol (PMorph), and 2-(1-(2-thiomorpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol (PTMorph) have been synthesized and screened for their antioxidant capacity, Cu-binding affinity, interaction with the Aß peptide and modulation of Aß peptide aggregation, and the ability to limit Aß1-42-induced neurotoxicity in human neuronal culture. The synthetic protocol and structural variance incorporated via click chemistry, highlights the influence of R-group modification on ligand-Aß interactions and neuroprotective effects. Overall, this study demonstrates that the phenol-triazole ligand scaffold can target multiple factors associated with AD, thus warranting further therapeutic development.

9.
Bioconjug Chem ; 28(5): 1363-1370, 2017 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-28402621

RESUMO

Altered lipid metabolism and extensive lipid storage in cells have been associated with various medical disorders, including cancer. The development of fluorescent probes that specifically accumulate in lipid deposits is therefore of great interest in order to study pathological processes that are linked to dysregulated lipogenesis. In the present study, we present a small fluorescent benzothiadiazole dye that specifically stains lipid droplets in living and fixated cells. The photophysical characterization of the probe revealed strong solvatochromic behavior, large Stokes shifts, and high fluorescent quantum yields in hydrophobic solvents. In addition, the fluorophore exhibits a nontoxic profile and a high signal-to-noise ratio in cells (i.e., lipid droplets vs cytosol), which make it an excellent candidate for studying lipid biology using confocal fluorescent microscopy.


Assuntos
Corantes Fluorescentes/química , Processamento de Imagem Assistida por Computador/métodos , Gotículas Lipídicas/química , Tiadiazóis/química , Humanos , Razão Sinal-Ruído , Espectrometria de Fluorescência
11.
Eur J Med Chem ; 114: 59-64, 2016 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-26974375

RESUMO

A scaffold approach has been used to develop somatostatin ß-turn mimetics based on chroman-4-one and chromone ring systems. Such derivatives could adopt conformations resembling type II or type II' ß-turns. Side chain equivalents of the crucial Trp8 and Lys9 in somatostatin were introduced in the 2- and 8-positions of the scaffolds using efficient reactions. Interestingly, this proof-of-concept study shows that 4 and 9 have Ki-values in the low µM range when evaluated for their affinity for the sst2 and sst4 receptors.


Assuntos
Materiais Biomiméticos/farmacologia , Cromanos/farmacologia , Cromonas/farmacologia , Receptores de Somatostatina/agonistas , Somatostatina/química , Somatostatina/farmacologia , Materiais Biomiméticos/química , Cromanos/química , Cromonas/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
12.
PLoS One ; 10(12): e0145013, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26698305

RESUMO

BACKGROUND: The AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer. MATERIALS AND METHODS: Whole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1. RESULTS: Genome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Perfilação da Expressão Gênica , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Serina-Treonina Quinases TOR/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Moleculares , Conformação Proteica , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Quinases S6 Ribossômicas 70-kDa/química , Proteínas Quinases S6 Ribossômicas 90-kDa/química , Taxa de Sobrevida , Células Tumorais Cultivadas
13.
Eur J Med Chem ; 85: 127-38, 2014 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-25078316

RESUMO

Inhibition or allosteric modulation of mitogen-activated protein kinase kinases MEK1 and MEK2 (MEK1/2) represent a promising strategy for the discovery of new specific anticancer agents. In this paper, structure-based design, beginning from the lead compound PD98059, was used to study potential structural modifications on the chromone structure in order to obtain highly potent derivatives that target the allosteric pocket in MEK1. Subsequently, a small series of PD98059 analogs were synthesized to provide a first generation of chromone-based derivatives that inhibit the activation of MEK1 with IC50 values as low as 30 nM in vitro. Complementary cellular studies also showed that two of the compounds in the series inhibit the activity of MEK1/2 with IC50 values in the nanomolar range (73-97 nM). In addition, compounds in this series were found to inhibit the proliferation of a small panel of human cancer cell lines.


Assuntos
Cromonas/química , Desenho de Fármacos , Flavonoides/química , Flavonoides/farmacologia , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Flavonoides/síntese química , Flavonoides/metabolismo , Humanos , MAP Quinase Quinase 1/química , MAP Quinase Quinase 2/química , Simulação de Acoplamento Molecular
14.
J Inorg Biochem ; 139: 106-16, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25019963

RESUMO

One of the hallmarks of Alzheimer's disease (AD) in the brain are amyloid-ß (Aß) plaques, and metal ions such as copper(II) and zinc(II) have been shown to play a role in the aggregation and toxicity of the Aß peptide, the major constituent of these extracellular aggregates. Metal binding agents can promote the disaggregation of Aß plaques, and have shown promise as AD therapeutics. Herein, we describe the syntheses and characterization of an acetohydrazone (8-H2QH), a thiosemicarbazone (8-H2QT), and a semicarbazone (8-H2QS) derived from 8-hydroxyquinoline. The three compounds are shown to be neutral at pH7.4, and are potent antioxidants as measured by a Trolox Equivalent Antioxidant Capacity (TEAC) assay. The ligands form complexes with Cu(II), 8-H2QT in a 1:1 metal:ligand ratio, and 8-H2QH and 8-H2QS in a 1:2 metal:ligand ratio. A preliminary aggregation inhibition assay using the Aß1-40 peptide showed that 8-H2QS and 8-H2QH inhibit peptide aggregation in the presence of Cu(II). Native gel electrophoresis/Western blot and TEM images were obtained to give a more detailed picture of the extent and pathways of Aß aggregation using the more neurotoxic Aß1-42 in the presence and absence of Cu(II), 8-H2QH, 8-H2QS and the drug candidate PBT2. An increase in the formation of oligomeric species is evident in the presence of Cu(II). However, in the presence of ligands and Cu(II), the results match those for the peptide alone, suggesting that the ligands function by sequestering Cu(II) and limiting oligomer formation in this assay.


Assuntos
Peptídeos beta-Amiloides/química , Cobre/química , Sequestradores de Radicais Livres/química , Oxiquinolina/análogos & derivados , Oxiquinolina/química , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Cristalografia por Raios X , Sequestradores de Radicais Livres/farmacologia , Humanos , Células Jurkat , Oxiquinolina/farmacologia , Agregados Proteicos , Bases de Schiff/química , Semicarbazonas/química , Semicarbazonas/farmacologia
15.
Mol Cancer Ther ; 12(8): 1526-36, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23699657

RESUMO

The insulin-like growth factor-1 (IGF-I) and its receptors play an important role in transformation and progression of several malignancies. Inhibitors of this pathway have been developed and evaluated but generally performed poorly in clinical trials, and several drug candidates have been abandoned. The cyclolignan picropodophyllin (PPP) has been described as a potent and selective IGF-IR inhibitor and is currently undergoing clinical trials. We investigated PPP's activity in panels of human cancer cell lines (e.g., esophageal squamous carcinoma cell lines) but found no effects on the phosphorylation or expression of IGF-IR. Nor was the cytotoxic activity of PPP related to the presence or spontaneous phosphorylation of IGF-IR. However, its activity correlated with that of known tubulin inhibitors, and it destabilized microtubule assembly at cytotoxic concentrations also achievable in patients. PPP is a stereoisomer of podophyllotoxin (PPT), a potent tubulin inhibitor, and an equilibrium between the two has previously been described. PPP could thus potentially act as a reservoir for the continuous generation of low doses of PPT. Interestingly, PPP also inhibited downstream signaling from tyrosine kinase receptors, including the serine/threonine kinase Akt. This effect is associated with microtubule-related downregulation of the EGF receptor, rather than the IGF-IR. These results suggest that the cytotoxicity and pAkt inhibition observed following treatment with the cyclolignan PPP in vitro result from microtubule inhibition (directly or indirectly by spontaneous PPT formation), rather than any effect on IGF-IR. It is also suggested that PPT should be used as a reference compound in all future studies on PPP.


Assuntos
Antineoplásicos/toxicidade , Podofilotoxina/análogos & derivados , Receptor IGF Tipo 1/antagonistas & inibidores , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias Esofágicas/metabolismo , Humanos , Microtúbulos/metabolismo , Fosforilação/efeitos dos fármacos , Podofilotoxina/toxicidade , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Moduladores de Tubulina/farmacologia
16.
J Med Chem ; 54(20): 7427-31, 2011 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-21905739

RESUMO

3-(4-Fluorophenyl)-2-(4-pyridyl)chromone derivatives were synthesized and evaluated as p38 MAP kinase inhibitors. Introduction of an amino group in the 2-position of the pyridyl moiety gave p38α inhibitors with IC(50) in the low nanomolar range (e.g., IC(50) = 17 nm). The inhibitors showed excellent selectivity profiles when tested on a panel of 62 kinases, as well as efficient inhibition of p38 signaling in human breast cancer cells.


Assuntos
Antineoplásicos/síntese química , Cromonas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama , Linhagem Celular Tumoral , Cromonas/química , Cromonas/farmacologia , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Modelos Moleculares , Relação Estrutura-Atividade
17.
Bioorg Med Chem ; 19(8): 2659-65, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21459004

RESUMO

A series of dihalogenated chalcones and structurally related dienones were synthesized and evaluated for their antiproliferative activity in 10 different cancer cell lines and for their effect on microtubule assembly. All compounds showed cytotoxic activity, with IC(50) values in the 5-280 µM range depending on the chalcone structure and the cell line. Five of the compounds were found to be tubulin polymerization inhibitors. In contrast, one of the compounds was found to stabilize tubulin to the same extent as the anticancer drug docetaxel. Molecular modeling suggested that the tubulin inhibitors bind to the colchicine binding site of ß-tubulin while the novel tubulin stabilization agent seems to interact with the paclitaxel binding site.


Assuntos
Antineoplásicos/síntese química , Chalconas/química , Chalconas/farmacologia , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/efeitos dos fármacos , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Chalconas/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cetonas , Polimerização , Relação Estrutura-Atividade , Tubulina (Proteína)/agonistas
18.
Chemistry ; 15(37): 9417-23, 2009 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-19670192

RESUMO

We present the synthesis and photophysical characterisation of a series of structurally diverse, fluorescent 2,6,8-trisubstituted 3-hydroxychromone derivatives with high fluorescence quantum yields and molar extinction coefficients. Two of these derivatives (9 and 10 a) have been studied as fluorophores for cellular imaging in HeLa cells and show excellent permeability and promising fluorescence properties in a cellular environment. In addition, we have demonstrated by photophysical characterisation of 3-isobutyroxychromone derivatives that esterification of the 3-hydroxyl group results in acceptable and useful fluorescence properties.


Assuntos
Cromonas/química , Corantes Fluorescentes/química , Cromonas/síntese química , Citometria de Fluxo , Células HeLa , Humanos , Microscopia de Fluorescência , Fotoquímica
19.
J Org Chem ; 74(7): 2755-9, 2009 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-19323574

RESUMO

A base-promoted condensation between 2-hydroxyacetophenones and aliphatic aldehydes has been studied. The reaction has been optimized to afford 2-alkyl-substituted 4-chromanones in an efficient manner using microwave heating. Performing the reaction using diisopropylamine in EtOH at 170 degrees C for 1 h gave moderate to high yields (43-88%). The 4-chromanones could be further converted into highly functionalized 2,3,6,8-tetrasubstituted chromones in which a 3-substituent (acetate, amine, or bromine) was introduced via straightforward chemical transformations.


Assuntos
Cromonas/síntese química , Micro-Ondas , Aldeídos/química , Alquilação , Cromonas/química , Estrutura Molecular
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