1,721,128 research outputs found
Design, synthesis and biological validation of epigenetic modulators of histone/protein deacetylation and methylation
Full text linkSmall-molecule inhibitors of histone deacetylase for the treatment of cancer and non-cancer diseases: a patent review (2011 - 2013).
No full textDNA methyltransferases Inhibitors from natural sources
No full textDNA methyltransferases (DNMTs) catalyze the methylation at cytosine-C5 mainly in a CpG dinucleotide context. Although DNA methylation is essential for fundamental processes like embryonic development or differentiation, aberrant expres- sion and/or activities of DNMTs are involved in several pathologies, from neurode- generation to cancer. DNMTs inhibition can arrest tumor growth, cells invasiveness
and induce differentiation, whereas their increased expression is shown in numerous cancer types. Moreover, hypermethy- lated promoters of tumor suppressor genes lead to their silencing. Hence, the use of specific inhibitors of DNMT might reactivate those genes and stop or even reverse the aberrant cell processes. To date, the only approved DNMTs inhibitors for therapy belong to the nucleoside-based family of drugs, but they display relevant side effects as well as high chemical instability. Thus, there is a keen interest actually exists to develop novel, potent and safe inhibitors possessing a non- nucleoside structure. Increasing literature evidence is highlighting that natural sources could help the researchers to achieve this goal. Indeed, several polyphenols, flavonoids, antraquinones, and others are described able to inhibit DNMTs activity and/or expression, thus decreasing the methylation/silencing of different genes involved in tumorigenesis. These events can lead to re-expression of such genes and to cell death in diverse cancer cell lines. Epigallocatechin-3-gallate (1) and laccaic acid A (11) resulted the most effective DNMT1 inhibitors with submicromolar IC50 values, acting as competi- tive inhibitors. Compound 1 and 11 both displayed gene demethylation and re-activation in several cancers. However, all of the natural compounds described in this review showed important results, from gene reactivation to cell growth inhibi- tion. Moreover, some of them displayed interesting activity even in rodent cancer models and very recently entered clini- cal trials
Facile synthesis of 4-acetyl-coumarins, -thiocoumarin and -quinolin-2(1H)-one via very high α-regioselective Heck coupling on tosylates
No full textAn efficient synthesis of a series of methyl ketones at the C4 position of coumarins, coumarin-containing heterocycles and analogous scaffolds is reported via very high α-regioselective Heck coupling using tosylates and in very high yields. Although α-regioselectivity in Heck coupling can be obtained with triflates as substrates, tosylates are less toxic, less expensive and, importantly, more stable. © 2011 Elsevier Ltd. All rights reserved
Histone deacetylase inhibitors (epigenetic alterations)Targeted Therapies for Hepatocellular Carcinoma
No full text
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
Polycomb repressive complex 2 modulation through the development of EZH2–EED interaction inhibitors and EED binders
Full text linkEpigenetics is nowadays a well-accepted area of research. In the last years, tremendous progress was made regarding molecules targeting EZH2, directly or indirectly. Recently tazemetostat hit the market after FDA-approval for the treatment of lymphoma. However, the impairment of EZH2 activity by orthosteric intervention has proven to be effective only in a limited subset of cancers. Considering the multiproteic nature of the PRC2 complex and the marked dependence of EZH2 functions on the other core subunits such as EED, in recent years, a new targeting approach ascended to prominence. The possibility to cripple the function of the PRC2 complex by interfering with its multimeric integrity fueled the interest in developing EZH2–EED protein–protein interaction and EED inhibitors as indirect modulators of PRC2-dependent methyltransferase activity. In this Perspective, we aim to summarize the latest findings regarding the development and the biological activity of these emerging classes of PRC2 modulators from a medicinal chemist’s viewpoint
Emerging approaches for histone deacetylase inhibitor drug discovery
No full textINTRODUCTION:
Histone deacetylases (HDACs) are key players in the mediation of gene expression for both cancerous and noncancerous malignancies. Overexpression of these enzymes has been demonstrated in numerous types of cancer with some enzyme isoforms also involved in neurological, inflammatory and viral pathologies. Hence, the development of HDAC inhibitors (HDACis) represents a promising approach for their treatment. Numerous chemical entities have been studied in the recent years and some of them have reached clinical trials.
AREAS COVERED:
This review summarizes the recent efforts in the drug development of HDACis and their potential application as therapeutic agents in cancerous, neurological, inflammatory and viral diseases.
EXPERT OPINION:
The development of novel potent and selective HDACis is ongoing. However, increased scientific effort is needed to aid the fight of specific types of cancerous or noncancerous disease with more selective agents required to avoid side effects during therapy. An interesting therapeutic approach is the use of HDACis in combination with other epigenetic target modulators to combine their therapeutic potential for a synergistic effect
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