130,580 research outputs found
Targeting histone demethylases: A new avenue for the fight against cancer
No full textIn addition to genetic disorders, epigenetic alterations have been shown to be involved in cancer, through misregulation of histone modifications. Miswriting, misreading, and mis-erasing of histone acetylation as well as methylation marks can be actually associated with oncogenesis and tumor proliferation. Historically, methylation of Arg and Lys residues has been considered a stable, irreversible process due to the slow turnover of methyl groups in chromatin. The discovery in recent years of a large number of histone Lys demethylases (KDMs, belonging to either the amino oxidase or the JmjC family) totally changed this point of view and suggested a new role for dynamic histone methylation in biological processes. Since overexpression, alteration, or mutation of a number of KDMs has been found in many types of cancers, such enzymes could represent diagnostic tools as well as epigenetic targets to modulate for obtaining novel therapeutic weapons against cancer. The first little steps in this direction are described here. © The Author(s) 2011
Le parole dell'arte. Ovvero quando l'opera, da sola, non basta
No full textQuesto lavoro prende le mosse da quelle opere d'arte che hanno comportato l'uccisione, il maltrattamento e l'uso di animali per la loro realizzazione e quindi quella tipologia di opere che richiede una determinata teoria per essere definita "d'arte". Si prende come riferimento la filosofia dell'arte di Arthur Danto per riflettere sulla necessità del rapporto tra opera e interpretazione nell'arte contemporanea. Se l'arte attuale si è (quasi) emancipata dai vincoli formali, dagli standard etici ed estetici che fino lai tempi delle avanguardie hanno regolamentato l' attività dell'artista, questa arte risulta essere, al tempo stesso, una sorta di arte ancora più dipendente da una esegesi, da una spiegazione e una interpretazione che devono far luce sul suo significato, il suo scopo, la sua intenzione. Tuttavia , se è vero che ciò che rende qualcosa un'opera d' arte è la sua relazione con il contesto costituito dalla storia e dalla teoria dell'arte e se è vero che un'interpretazione che si basa su questo tipo di conoscenza fa si che un oggetto fisico venga visto come un'opera d'arte, è anche vero che le cornici storiche tendono a non definire le "caratteristiche distintive " dell'arte lasciando, in sostanza, irrisolta la questione posta dal problema dei criteri di riconoscimento artistico.This paper moves from those works of art that include the killing, the ill-treatment and the use of dead animals and therefore it starts from the artifacts whose status of art is difficult to understand in order to discuss the role and power of the theory in the art world. It considers in particular the philosophy of art of Arthur Danto to reflect on the necessity of the relationship between work and interpretation in contemporary art. If the current art has earned (hardly) the freedom from formal constraints, from the ethical and aesthetic standards that until the avant-garde art have regulated the activity of the artist, this art turns out to be, at the same time, a kind of art even more dependent from an exegesis, from an explanation and an interpretation that have to shed light on its meaning, its purpose, its intention. Yet if it is true that what makes something a work of art is its relationship with the context formed by the history and by theory of art and if it is true that an interpretation that is based on this type of knowledge allows a physical object to be seen as a work of art, it is also true that the frames that appeal to history tend not to clearly define the "distinctive characteristics" of art, leaving unresolved, in essence, the question posed by the problem of the recognition criteria
Discovery of Salermide-Related Sirtuin Inhibitors: Binding Mode Studies and Antiproliferative Effects in Cancer Cells Including Cancer Stem Cells
No full textRotili, D., Tarantino, D., Nebbioso, A., Paolini, C., Huidobro, C., Lara, E., Mellini, P., Lenoci, A., Pezzi, R., Botta, G., Lahtela-Kakkonen, M., Poso, A., Steinkühler, C., Gallinari, P., De Maria, R., Fraga, M., Esteller, M., Altucci, L., Mai, A
Natural products from higher plants and marine organisms as sources of new anticancer agents: synthesis and biological evaluation
No full textAbstract part A: The dysregulation of the Hedgehog (Hh) signaling pathway plays a pivotal role in the generation and cell-manteinance of many human cancers. Gli transcription factors, the final effectors of the pathway, represent the most promising target for the development of new drugs targeting the Hh pathway in tumors. In a previous work, a natural isoflavone, glabrescione B (GlaB) (I), was identified as the first small molecule binding Gli1. It is able to inhibit the transcriptional activity of Gli1, by interfering with its interaction with DNA. In order to perform further studies on the mechanism of action of GlaB (I) we developed a total synthesis, while NMR studies demonstrated the interaction of GlaB with Gli1
Biological studies have demonstrated its ability to interfere with the activity of Gli1 by inhibiting the growth of Gli-dependent-Hh-dependent tumor cells such as medulloblastoma (MB) and basal cell carcinoma (BCC) both in vitro and in allograft mouse models.
In addition, our new synthetic route, which encompasses just three steps with an overall yield of 15%, provided an efficient synthetic means to enable the investigation of the role of GlaB ring-B in the interaction Gli1-GlaB. In fact, our synthetic strategy allowed the preparation of several GlaB derivativesin order to elucidate the structure-activity relationships (SARs) and to clarify the molecular mechanism underlying its Hedgehog signalling modulation.Abstract part B: The second part of this PhD thesis describes the work I have carried out during my research stay abroad at Swiss Federal Institute of Technology (ETH) in Zürich (Switzerland) in Prof. Dr. Karl-Heinz Altmann's laboratory. Marine natural products show higher incidence of bioactivity compared to terrestrial natural products. This is due to a high degree of chemical novelty and their high dilution in ocean water. (+)-Dactylolide (I) was isolated by Riccio and co-workers from a sponge of the genus Dactylospongia, collected off the coast of Vanuatu islands, in the South Pacific Ocean. The absolute and the relative configuration at C19 of the compound remained unassigned. The assignment of the relative and absolute configuration of (+)-dactylolide (I) is based on its first total synthesis by Smith and co-workers. As had been described for the natural product, synthetic dactylolide has been found to be dextrorotatory, but the magnitude of the specific rotation reported for the natural product and synthetic I were significantly different from each other. In addition, the discrepancies between the 13C-NMR spectra of synthetic and natural (+)-dactylolide (if ever so slight), also leave open the possibility that the configuration of C19 in natural (+)-dactylolide is R and not S (i. e. natural dactylolide could have the structure II instead of I). In order to demonstrate that, a total synthesis of both compounds was established.
(+)-Dactylolide (I) is related to (-)-zampanolide (III), another marine macrolide. The latter shows low nanomolar cytotoxicity against both drug-sensitive and multi-drug resistant cancer cell lines, and induces microtubule bundle formation. While (-)-zampanolide (III) is a nM inhibitor of cancer cell growth in vitro, not many data about the activity of (+)-dactylolide (I) have been published. On the other hand, the biological activity of synthetic (-)-dactylolide (ent-I) is well known. This compound exhibits sub-μM IC50 values against a multitude of cancer cell lines, although (–)-zampanolide (III) is still 100- to 300-fold more potent. At the same time, not even synthetic (+)-zampanolide (ent-III) has ever been tested and the importance of the configuration of the macrocycle for the potency of dextrorotatory compounds remains unclear. Our goal was to synthesize (+)-dactylolide (I) and (+)-zampanolide (ent-III), in order to investigate how the macrocycle configuration would affect the biological activity of the compounds
Lysine acetyltransferase inhibitors from natural sources
No full textAcetylation of histone and non-histone protein lysine residues has been widely described as a critical modulator of several cell functions in humans. Lysine acetyltransferases (KATs) catalyse the transfer of acetyl groups on substrate proteins and are involved in multiple physiological processes such as cell signalling, metabolism, gene regulation, and apoptosis. Given the pivotal role of acetylation, the alteration of KATs enzymatic activity has been clearly linked to various cellular dysfunctions leading to several inflammatory, metabolic, neurological, and cancer diseases. Hence, the use KAT inhibitors (KATi) has been suggested as a potentially successful strategy to reverse or prevent these conditions. To date, only a few KATi have proven to be potential drug candidates, and there is still a keen interest in designing molecules showing drug-like properties from both pharmacodynamics and pharmacokinetics point of view. Increasing literature evidence has been highlighting natural compounds as a wide source of molecular scaffolds for developing therapeutic agents, including KATi. In fact, several polyphenols, catechins, quinones, and peptides obtained from natural sources (including nuts, oils, root extracts, and fungi metabolites) have been described as promising KATi. Here we summarize the features of this class of compounds, describing their modes of action, structure-activity relationships and (semi)-synthetic derivatives, with the aim of assisting the development of novel more potent, isoform selective and drug-like KATi
Emerging therapeutic potential of SIRT6 modulators
No full textSirtuin 6 (SIRT6) is an NAD+-dependent protein deacylase and mono-ADP-ribosyltransferase of the sirtuin family with a wide substrate specificity.In vitroandin vivostudies have indicated that SIRT6 overexpression or activation has beneficial effects for cellular processes such as DNA repair, metabolic regulation, and aging. On the other hand, SIRT6 has contrasting roles in cancer, acting either as a tumor suppressor or promoter in a context-specific manner. Given its central role in cellular homeostasis, SIRT6 has emerged as a promising target for the development of small-molecule activators and inhibitors possessing a therapeutic potential in diseases ranging from cancer to age-related disorders. Moreover, specific modulators allow the molecular details of SIRT6 activity to be scrutinized and further validate the enzyme as a pharmacological target. In this Perspective, we summarize the current knowledge about SIRT6 pharmacology and medicinal chemistry and describe the features of the activators and inhibitors identified so far
Sirt4: a multifaceted enzyme at the crossroads of mitochondrial metabolism and cancer
No full textSirtuins are NAD+-dependent deacylases that play crucial roles in the regulation of cellular metabolism, and as a result, are implicated in several diseases. The mitochondrial sirtuin Sirt4, for a long time considered as mainly a mono-ADP-ribosyltransferase, recently has shown a robust deacylase activity in addition to the already accepted substrate-dependent lipoamidase and deacetylase properties. Through these and likely other enzymatic and non-enzymatic activities, Sirt4 closely controls various metabolic events, and its dysregulation is linked to various aging-related disorders, including type 2 diabetes, cardiac hypertrophy, non-alcoholic fatty liver disease, obesity, and cancer. For its capability to inhibit glutamine catabolism and for the modulation of genome stability in cancer cells in response to different DNA-damaging conditions, Sirt4 is proposed as either a mitochondrial tumor suppressor or a tumor-promoting protein in a context-dependent manner. In addition to what is already known about the roles of Sirt4 in different biological settings, further studies are certainly still needed in order to validate this enzyme as a new potential target for various aging diseases
Recent advances in epigenetic proteolysis targeting chimeras (Epi-PROTACs)
No full textPROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules that trigger the poly-ubiquitination of the protein of interest (POI) inducing its degradation via the recruitment of the ubiquitin-proteasome system, thus suppressing the POI's intracellular levels and indirectly all its functions. Recently, one of the fields where the protein knockdown induced by PROTACs has demonstrated to serve as a promising biochemical tool and to provide new opportunities for drug discovery is the epigenetics (epi-PROTACs). A full inhibition of the functions of all domains of a specific epigenetic POI (e-POI), rather than just the block of its catalytic/single domain activity, is in fact a new more effective modality to hit an e-POI and, in principle, the complex it belongs to, and potentially to treat the related diseases, first cancer. In this review, we will present the most relevant progresses made, especially in the last two years, in the application of PROTACs technology to the three main classes of e-POIs: “writers”, “erasers” and “readers”. Emphasis will be devoted to the medicinal chemistry aspects of the epi-PROTACs design, preparation, and optimization and to the comparison with small molecule epi-drugs for both epi-targets functional annotation and potential anticancer therapy purposes
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