RESUMO
In this work, we describe how stereochemically complex polycyclic compounds can be generated by applying a synthetic sequence comprising an intramolecular Ugi reaction followed by a Pictet-Spengler cyclization on steroid-derived scaffolds. The resulting compounds, which combine a fragment derived from a natural product and a scaffold not found in nature. are both structurally distinct and globally similar to natural products at the same time, and interrogate an alternative region of the chemical space. One of the new compounds showed significant antiproliferative activity on HepG2 cells through a caspase-independent cell-death mechanism, an appealing feature when new antitumor compounds are searched.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Caspases/metabolismo , Isoquinolinas/farmacologia , Piperazinas/farmacologia , Esteroides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo , Esteroides/síntese química , Esteroides/químicaRESUMO
Evolution of metabolism is a longstanding yet unresolved question, and several hypotheses were proposed to address this complex process from a Darwinian point of view. Modern statistical bioinformatic approaches targeted to the comparative analysis of genomes are being used to detect signatures of natural selection at the gene and population level, as an attempt to understand the origin of primordial metabolism and its expansion. These studies, however, are still mainly centered on genes and the proteins they encode, somehow neglecting the small organic chemicals that support life processes. In this work, we selected steroids as an ancient family of metabolites widely distributed in all eukaryotes and applied unsupervised machine learning techniques to reveal the traits that natural selection has imprinted on molecular properties throughout the evolutionary process. Our results clearly show that sterols, the primal steroids that first appeared, have more conserved properties and that, from then on, more complex compounds with increasingly diverse properties have emerged, suggesting that chemical diversification parallels the expansion of biological complexity. In a wider context, these findings highlight the worth of chemoinformatic approaches to a better understanding the evolution of metabolism.
Assuntos
Quimioinformática , Seleção Genética , Eucariotos , Evolução Molecular , Genoma , FilogeniaRESUMO
In this work we describe not previously explored binding studies on the reversible interaction of benzoxaborole with ligands of medical and pharmaceutical interest such as nucleosidic drugs gemcitabine and capecitabine, as well as the hydrophobic chemotherapeutic doxorubicin. We include functional derivatives of benzoxaborole such as a near infrared fluorescent boronolectine, Cy-Bx, The dynamic covalent interaction in physiological conditions was assessed by spectroscopic techniques yielding moderate to high binding affinities. The cytotoxic activity of the drugs upon conjugation to the boronolectins was evaluated revealing significant influence of the bioconjugation status on the cellular viability. The availability of the conjugate for cellular uptake and localization in the model cancer cell line HeLa was assessed by fluorescence imaging. Benzoxaborole and the fluorescent boronolectin Cy-Bx, proved to be versatile conjugation tools for 1,2 and 1,3-diol containing pharmacophores as well as bioisosteric forms such as 1,2-hydroxyamino, envisioning these small boronolectins as components in systems for drug release with tracking capability.
Assuntos
Antineoplásicos/farmacologia , Benzamidas/química , Compostos de Boro/farmacologia , Doxorrubicina/farmacologia , Nucleosídeos/química , Nucleosídeos/metabolismo , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/química , Compostos de Boro/química , Proliferação de Células , Doxorrubicina/química , Liberação Controlada de Fármacos , Corantes Fluorescentes/química , Células HeLa , Humanos , Monossacarídeos/químicaRESUMO
We report the synthesis of a near-infrared (NIR) fluorescent pH probe with a remarkable Stokes shift (â¼135 nm) based on a tricarbocyanine (Cy-PIP). The fluorescent molecule was anchored to SiO2 nanoparticles (Cy-PIP@SiO2) and is capable of monitoring pH changes within the physiological range (pH 6-8). The Cy-PIP@SiO2 nanoparticles were successfully internalized by HeLa cells as shown by fluorescence confocal microscopy, while flow cytometry revealed pH fluctuations during the endocytic pathway.
RESUMO
Recent studies have shown that low concentrations of brassinolide induce a rapid generation of nitric oxide in mesophyll cells of maize leaves, which can be easily detected by fluorimetric methods. In this work we describe a series of natural and synthetic brassinosteroids that are able to trigger in vitro NO production in tomato cells that exhibits dose-response behavior. We propose that this effect can be used to develop a new rapid and very sensitive bioassay for brassinosteroid activity that offers several advantages when compared to the current methodologies.
Assuntos
Bioensaio/métodos , Brassinosteroides/análise , Fluorometria/métodos , Óxido Nítrico/metabolismo , Células Vegetais/metabolismo , Folhas de Planta/metabolismo , Esteroides Heterocíclicos/análise , Zea mays/metabolismo , Folhas de Planta/citologia , Zea mays/citologiaRESUMO
In this paper we report the synthesis of four ring-A difluorinated analogs of brassinosteroids. The bioactivity of these new compounds was evaluated using the rice lamina inclination test. The results show that one of these analogs elicits a bioactivity comparable to that of 28-homocastasterone, a highly active natural brassinosteroid. This finding suggests that both hydroxyls at C-2 and C-3 in active brassinosteroids are involved as hydrogen bond acceptors in their interactions with the cellular receptor.
Assuntos
Esteroides/química , Esteroides/síntese química , Brassinosteroides , Colestanóis/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Esteroides Heterocíclicos/química , Relação Estrutura-AtividadeRESUMO
In this paper we report the synthesis of four fluorinated analogues of brassinosteroids in which fluorine was introduced stereoselectively at C-2. The bioactivity of these new compounds was evaluated using the rice lamina inclination test. The results show that two of these analogues elicit high bioactivity, suggesting the involvement of hydrogen bond interactions between the active brassinosteroids and their cellular receptor.
Assuntos
Colestanóis/síntese química , Colestanóis/farmacologia , Halogenação/efeitos dos fármacos , Esteroides Heterocíclicos/síntese química , Esteroides Heterocíclicos/farmacologia , Bioensaio , Brassinosteroides , Colestanóis/química , Oryza/efeitos dos fármacos , Esteroides Heterocíclicos/químicaRESUMO
In this paper we report the use of an intramolecular Ugi reaction to synthesize new 4-azacholestanes diversely substituted both at N-4 and C-5. Both the scope and the stereochemical outcome of this approach were studied by varying the nature of the components necessary for this multicomponent reaction. In sight of our results we concluded that this methodology can be applied to obtain 4-azasteroids targeted to find new biologically active compounds.
Assuntos
Azasteroides/síntese química , Azasteroides/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
In a previous work our group showed that some synthetic stigmastanes may play a role in immune-mediated inflammation. In this paper we report the syntheses of a series of new steroidal compounds derived from dehydroepiandrosterone and stigmasterol, and the evaluation of their in vitro inhibitory activity of the TNF-alpha production by macrophages. A preliminary qualitative structure-activity relationship was established.