RESUMO
Besides their widespread use in coordination chemistry, 2,2'-bipyridines are known for their ability to undergo cis-trans conformational changes in response to metal ions and acids, which has been primarily investigated at the molecular level. However, the exploitation of such conformational switching in self-assembly has remained unexplored. In this work, the use of 2,2'-bipyridines as acid-responsive conformational switches to tune supramolecular polymerization processes has been demonstrated. To achieve this goal, we have designed a bipyridine-based linear bolaamphiphile, 1, that forms ordered supramolecular polymers in aqueous media through cooperative aromatic and hydrophobic interactions. Interestingly, addition of acid (TFA) induces the monoprotonation of the 2,2'-bipyridine moiety, leading to a switch in the molecular conformation from a linear (trans) to a V-shaped (cis) state. This increase in molecular distortion along with electrostatic repulsions of the positively charged bipyridine-H+ units attenuate the aggregation tendency and induce a transformation from long fibers to shorter thinner fibers. Our findings may contribute to opening up new directions in molecular switches and stimuli-responsive supramolecular materials.
RESUMO
Capsaicin (CAP) has been long known for its analgesic properties and more recently for its antitumor activity in various cell types. However, its pungency and the high doses needed to achieve a significant activity have precluded its application in cancer therapy. Herein, we propose a straightforward novel strategy to improve the antitumor effect of CAP based on the enhancement of its aggregation propensity in aqueous media by covalent attachment of a BODIPY (BDP) dye. The target CAP-BDP 1 self-assembles in aqueous solutions into weakly fluorescent globular assemblies that become highly emissive upon cell uptake-induced disassembly. Remarkably, due to the improved delivery to the tumour tissue upon aggregation, we have succeeded in reducing the doses of CAP-based drugs in vivo in prostate cancer by two orders of magnitude while maintaining a substantial antitumor activity.
Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/química , Capsaicina/farmacologia , Corantes Fluorescentes/química , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/química , Compostos de Boro/síntese química , Capsaicina/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/síntese química , Humanos , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Células PC-3 , Neoplasias da Próstata/patologiaRESUMO
Cell internalization is a major issue in drug design. Although squaramide-based compounds are receiving much attention because of their interesting bioactivity, cell uptake and trafficking within cells of this type of compounds are still unknown. In order to monitor the cell internalization process of cyclosquaramide compounds we have prepared two fluorescent probes by covalently linking a fluorescent dye (BODIPY derivative or fluorescein) to a noncytotoxic cyclosquaramide framework. These two probes (C2-BDP and C2-FITC) rapidly internalize across live cell membranes through endocytic receptor-mediated mechanisms. Due to its higher fluorescence and photochemical stability, C2-BDP is a superior dye than C2-FITC. C2-BDP remains sequestered in late endosomes allowing their fast and selective imaging in various live cell types. Cyclosquaramide-cell membrane interactions facilitate cell uptake and have been investigated by binding studies in solution as well as in live cells. Cyclosquaramide 1 (C2-BDP) can be used as a highly fluorescent probe for the rapid and selective imaging of late endosomes in live cells.
Assuntos
Amidas/química , Ciclobutanos/química , Ciclobutanos/metabolismo , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Animais , Transporte Biológico , Compostos de Boro/química , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Modelos Moleculares , Conformação Molecular , Peso Molecular , Células NIH 3T3 , Processos FotoquímicosRESUMO
New tripodal squaramide-based hosts have been synthesised and structurally characterised by spectroscopic methods. In 2.5 % (v/v) [D(6)]DMSO in CDCl(3), compound 4 formed dimeric assemblies [log K(dim)=3.68(8)] as demonstrated by (1)Hâ NMR spectroscopy and UV dilution experiments. AFM and SEM analyses revealed the formation of a network of bundled fibres, which indicates a preferential mechanism for aggregation. These C(3)-symmetric tripodal hosts exhibited two different and mutually exclusive modes of binding, each one easily accessible by simultaneous reorientation of the squaramide groups. In the first, a convergent disposition of the NH squaramide protons allowed the formation of an array of N-Hâ â â X(-) hydrogen bonds with anions. In the second mode, reorientation of carbonyl squaramide groups allowed multiple C=Oâ â â H interactions with ammonium cations. The titration of 4 with different tetraalkylammonium iodides persistently showed the formation of 1:1 complexes, as well as 1:2 and 1:3 complexes. The corresponding stoichiometries and binding affinities of the complexes were evaluated by multi-regression analysis. The formation of high-order complexes, supported by ROESY, NOESY and mass spectrometry experiments, has been attributed to the insertion of NR(4)I ion pairs between the carbonyl and NH protons of the squaramide groups located in adjacent arms of 4. The observed effects reflect the induction of significant conformational changes in the hosts, mainly in relation to the relative orientation of the squaramide groups adapting their geometries to incoming ion-pair complementary substrates. The results presented herein identify and fully describe two different modes of ion-pair recognition aimed at directing conformational transitions in the host, therefore establishing a base for controlling more elaborate movements of molecular devices through ion-pair recognition.
RESUMO
The ß-turn unit is one of the most important secondary structure elements in proteins. The access to new conformationally controlled foldable modules can afford compounds with interesting bioactivities. Here, we describe a new family of peptido-squaramide foldable modules based on the considerable potential of the squaramide unit as a hydrogen bond donor and acceptor as well as the low rotational barrier of the C-N bond. The conformational analysis by NMR of these modules in chloroform and acetonitrile solution shows that a disecondary squaramide with the 4-aminobutyric acid in one of its substituents can mimic the ß-turn structure driven by the formation of an intramolecular hydrogen bonded ten-membered ring. This structure, although flexible, has been successfully combined with dipeptide chains to induce the formation of a hairpin-like structure driven by the formation of several cross-strand intramolecular hydrogen bonds.
Assuntos
Amidas/química , Materiais Biomiméticos/química , Peptídeos/química , Ligação de Hidrogênio , Modelos Moleculares , Conformação MolecularRESUMO
Oligophenyleneethynylenes (OPEs) are prominent building blocks with exciting optical and supramolecular properties. However, their generally small spectroscopic changes upon aggregation make the analysis of their self-assembly challenging, especially in the absence of additional hydrogen bonds. Herein, by investigating a series of OPEs of increasing size, we have unravelled the role of the conjugation length on the self-assembly properties of OPEs.
RESUMO
Herein we report the design, synthesis and assessment of the first example of a squaramide-based self-immolative system triggered by an enzymatic reduction. We have proved that the release of the alkylating agent N',N'-(bis(2-chloroethyl)benzene)-1,4-diamine (ANM) provokes a dramatic reduction of the survival factor in glioblastoma cells, evidencing the suitability of the squaramide-based spacer for drug delivery applications.
Assuntos
Preparações de Ação Retardada , Quinina/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Cinética , Estrutura Molecular , Quinina/química , Análise Espectral/métodosRESUMO
Heart failure (HF) patients have high 30-day readmission rates with high costs and poor quality of life. This study investigated the impact of a framework blending Lean Sigma, design thinking, and Lean Startup on 30-day all-cause readmissions among HF patients. This was a prospective study in an academic hospital in Baltimore, Maryland. Thirty-day all-cause readmission was assessed using the hospital's electronic medical record. The baseline readmission rate for HF was 28.4% in 2010 with 690 discharges. The framework was developed and interventions implemented in the second half of 2011. The impact of the interventions was evaluated through 2012. The rate declined to 18.9% among 703 discharges (P < .01). There was no significant change for non-HF readmissions. This study concluded that methodologies from technology and manufacturing companies can reduce 30-day readmissions in HF, demonstrating the potential of this innovations framework to improve chronic disease care.
Assuntos
Insuficiência Cardíaca/terapia , Readmissão do Paciente/estatística & dados numéricos , Melhoria de Qualidade , Idoso , Registros Eletrônicos de Saúde , Feminino , Humanos , Comunicação Interdisciplinar , Tempo de Internação/estatística & dados numéricos , Masculino , Educação de Pacientes como Assunto , Estudos Prospectivos , Fatores de RiscoRESUMO
A novel tertiary squaramido-based reverse-turn module SQ is reported, and its conformational properties are evaluated. This module is easily incorporated into a α-peptide sequence by conventional solid-phase peptide synthesis. The structure characterization of the hybrid squaramido-peptide 4 is described, showing that the turn segment induces the formation of hairpin structures in water through the formation of both αSQ- and ßSQ-turns.
Assuntos
Amidas/química , Peptídeos/química , Sequência de Aminoácidos , Ligação de Hidrogênio , Conformação Molecular , Estrutura MolecularRESUMO
Access to basic drugs is a major issue in developing countries. Chagas disease caused by Trypanosoma cruzi is a paradigmatic example of a chronic disease without an effective treatment. Current treatments based on benznidazole and nifurtimox are expensive, ineffective, and toxic. N,N'-Squaramides are amide-type compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites. When combined with amine and carboxylic groups, squaramide compounds have increased solubility and therefore make suitable therapeutic agents. In this work, we introduce a group of Lipinski's rule of five compliant squaramides as candidates for treating Chagas disease. The in vivo studies confirmed the positive expectations arising from the preliminary in vitro studies, revealing compound 17 to be the most effective for both acute and chronic phases. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-Chagasic agent.
Assuntos
Doença de Chagas/tratamento farmacológico , Ciclobutanos/síntese química , Diaminas/síntese química , Tripanossomicidas/síntese química , Animais , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Chlorocebus aethiops , Ciclobutanos/farmacologia , Ciclobutanos/toxicidade , Diaminas/farmacologia , Diaminas/toxicidade , Feminino , Terapia de Imunossupressão , Camundongos , Camundongos Endogâmicos BALB C , Relação Estrutura-Atividade , Tripanossomicidas/farmacologia , Tripanossomicidas/toxicidade , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/metabolismo , Trypanosoma cruzi/ultraestrutura , Células VeroRESUMO
We report the synthesis and biological evaluation of a new series of oligosquaramide-based macrocycles as anticancer agents. Compound 7, considered as representative of this series, exhibited significant antiproliferative activity against the NCI-60 human tumor cell line panel, with IC(50) values ranging from 1 to 10â µM. The results show that sensitivity to cyclosquaramides is clearly dependent on cell type, underscoring a degree of biological selectivity. The observed antiproliferative effects appear to be related to deregulation of protein phosphorylation, as compounds 7 and 8 are effective inhibitors of several important kinases such as ABL1, CDK4, CHK1, PKC, c-MET, and FGFR, among others. The corresponding acyclic oligosquaramides and smaller cyclosquaramides did not show antitumor activity, suggesting that a macrocyclic structure with minimal molecular size plays a key role in the observed antitumor activity.