1,720,963 research outputs found
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL G9A INHIBITORS FROM A SCAFFOLD HOPPING APPROACH
No full textThe lysine methyltransferase G9a (also named euchromatin histone methyltransferase 2, EHMT2) is primarily responsible for the dimethylation of lysine 9 on histone H3 (H3K9). Several reports have
highlighted its link to a variety of cancers. In particular, it has been shown that G9a is crucial for the oncogenic role of the repressor element (RE)-1 silencing transcription factor (REST) in the pediatric brain tumor medulloblastoma. Only a few among the selective inhibitors of G9a reported to date are useful chemical probes for cell-based and animal studies. Starting from the inhibitor UNC0638,3 we applied a scaffold hopping approach to develop novel chemical entities endowed with high affinity towards the G9a. In particular, we replaced the quinazoline core, typical of most of the reported inhibitors, with 1,4-benzodiazepine nucleus, known to be a privileged structure. We chose the 3,4-dihydro-5H-benzo[e][1,4]diazepin-5-one scaffold, that can be obtained through an efficient and gram-scale continuous-flow protocol, previously optimized by our group.4 Moreover, this scaffold could be easily decorated to provide a number of highly functionalized potential ligands. To validate our approach, we designed and synthesized a small library of UNC0638 analogues. All the compounds were tested through a peptide-based AlphaLISA, measuring the levels of H3K9 dimethylation
A continuous-flow synthesis of 1,4-benzodiazepin-5-ones, privileged scaffolds for drug discovery
No full textAn efficient and gram-scale continuous-flow protocol for the synthesis of the privileged structure 3,4-dihydro-5H-benzo[e][1,4]diazepin-5-one is reported. If compared to the traditional metal mediated non-catalytic reduction procedure, this approach is high yielding and does not require purification steps and therefore could be conveniently used for the generation of compound libraries for drug discovery
Expanding the quinazoline ring to 3H-benzo[e][1,4]diazepine: development of new and selective G9a inhibitors
No full textHistone lysine methyltransferases have crucial roles in a number of biological processes and human diseases by controlling gene expression and chromatin state. Within this family, the lysine methyltransferase G9a has emerged as a critical player in several pathologic states, mainly due to its important role in the silencing of tumour suppressor genes and in the regulation of other chromatin events (1). Despite the extensive research for new chemical entities, to date there is a low number of G9a chemical probes suitable for cell-based and animal studies, only bearing to the quinazoline class and among all the UNC0638 is the most used and best characterized compound (2).
Keeping this in mind and pursuing our efforts toward the identification of potent and selective histone lysinemethyltransferases inhibitors, we replaced the quinazoline moiety of the UNC0638 with a benzodiazepine framework, obtaining the EML741.
Herein we present the design and synthesis of the EML741 and its inhibitory activity toward G9a HMTase as well as its selectivity profile on other epigenetic enzymes. Moreover, we report the ability of EML741 to lower the G9a activity level in tumor cell lines
Identification of new inhibitors of PRMTs by a multi-substrate-adduct approach
No full textThe methylation of arginine residues is a prevalent posttranslational modification found in both nuclear and cytoplasmic proteins, which is involved in a number of different cellular processes, including transcriptional regulation, RNA metabolism, and DNA damage repair. Enzymes of the protein arginine N-methyltransferase (PRMT) family catalyze the transfer of a methyl group from the donor S-adenosyl-L-methionine (SAM or AdoMet) to the guanidinium side chain of arginine residues in the target protein. Despite extensive research aimed at better understand the role of PRMTs in physiological and pathological pathways, there have been only a few publications to date describing small-molecule chemical modulators of the PRMTs. A few years ago, starting from AMI-1 (the first selective inhibitor of PRMTs)1 we identified EML108, which was characterized by an improved selectivity profile among methyltransferases and a good cellular activity.2 Moreover, docking studies clearly showed that EML108 bind SAM and arginine pocket without fully occupying them. Starting from this evidence, we herein report the design and the synthesis of new PRMTs inhibitors based on the naphthalene scaffold of EML108. Firstly, we prepared some derivatives bearing a guanidine moiety connected to the naphthalene scaffold via a variable linker. After optimization, we further functionalized this scaffold with an adenosine moiety (Figure 1). This multi-substrate-adduct approach lead to the identification of new sub-micromolar inhibitors of the arginine methyltransferase PRMT1
Progress in the Development of Lysine Methyltransferase SETD8 Inhibitors
No full textSETD8/SET8/Pr-SET7/KMT5A is the only known lysine methyltransferase that monomethylates lysine 20 of histone H4 (H4K20) in vivo. The methyltransferase activity of SETD8 has been implicated in many essential cellular processes, including DNA replication, DNA damage response, transcription modulation, and cell cycle regulation. In addition to H4K20, SETD8 monomethylates non-histone substrates including proliferating cell nuclear antigen and p53. During the past decade, different structural classes of inhibitors targeting various lysine methyltransferases have been designed and developed. However, the development of SETD8 inhibitors is still in its infancy. This review covers the progress made to date in inhibiting the activity of SETD8 by small molecules, with an emphasis on their discovery, selectivity over other methyltransferases, and cellular activity
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Design, synthesis and biological evaluation of new small-molecule modulators of proein lysine methyltransferases (PKMTs)
Full text link2016 - 2017Histone lysine methyltransferases have crucial roles in a number of biological processes and human diseases by controlling gene expression and chromatin state. Within this family, the lysine methyltransferase G9a has emerged as critical player in several pathologic states, particularly because of its important role in the silencing of tumor suppressor genes and in the regulation of other chromatin events. The low number of G9a chemical probes suitable for cell-based and animal studies, as well as the limited chemical diversity demand for the development of new modulators. In this thesis, two different approaches aimed at the identification of novel chemotypes for the modulation of G9a are presented. On one hand, from a medicinal chemistry prospective, we considered the modification of the central core of the potent and selective inhibitor UNC0638, resulting in a 1,4-benzodiazepine derivative EML741. To validate the approach, we designed and synthesized a small set of ring-expanded derivatives and tested their activity in vitro. Peptide-based biochemical assays (AlphaLISA) validated our design, as compound EML741 preserves the activity of the parent compound. In fact, EML741 is a G9a competitive inhibitor with respect to substrate endowed with potent activity and selectivity. In addition, EML741 showed favorable physico-chemical properties as it is quite soluble and chemical stable in aqueous media, and exhibited a membrane permeability profile (PAMPA and PAMPA-BBB) better than the parent compound UNC0638... [edited by Author]XXX cicl
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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