http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
Schnekenburger, Michael,Goffin, Eric,Lee, Jin-Young,Jang, Jun Young,Mazumder, Aloran,Ji, Seungwon,Rogister, Bernard,Bouider, Nafila,Lefranc, Florence,Miklos, Walter,Mathieu, Vé,ronique,de Tullio American Chemical Society 2017 Journal of medicinal chemistry Vol.60 No.11
<P>A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells. On the basis of computational docking combined to in vitro sirtuin 1/2 inhibition assays, we selected compound 18 [R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea] which displays a potent anti.proliferative activity on various glioma cell types, assessed by quantitative videomicroscopy, eventually triggering senescence. The impact on normal glial cells was lower with a selectivity index of >10. Furthermore, human U373 and Hs683 glioblastoma cell lines served to demonstrate the inhibitory activity of 18 against histone deacetylase (HDAC) class III sirtuins 1 and 2 (SIRT1/2) by quantifying acetylation levels of histone and non-histone proteins. The translational potential of 18 was validated by an NCI-60 cell line screen and validation of growth inhibition of drug resistant cancer cell models. Eventually, the anticancer potential of 18 was validated- in 3D glioblastoma spheroids and in vivo by zebrafish xenografts. In summary, compound 18 is the first representative of a new class of SIRT inhibitors opening new perspectives in the medicinal chemistry of HDAC inhibitors.</P>
Plant-derived epigenetic modulators for cancer treatment and prevention
Schnekenburger, M.,Dicato, M.,Diederich, M. Pergamon Press ; Elsevier Science Ltd 2014 BIOTECHNOLOGY ADVANCES Vol.32 No.6
Carcinogenesis is a complex and multistep process that involves the accumulation of successive transformational events driven by genetic mutations and epigenetic alterations that affect major cellular processes and pathways such as proliferation, differentiation, invasion and survival. Massive deregulation of all components of the epigenetic machinery is a hallmark of cancer. These alterations affect normal gene regulation and impede normal cellular processes including cell cycle, DNA repair, cell growth, differentiation and apoptosis. Since epigenetic alterations appear early in cancer development and represent potentially initiating events during carcinogenesis, they are considered as promising targets for anti-cancer interventions by chemopreventive and chemotherapeutic strategies using epigenetically active agents. In this field, plant-derived compounds have shown promise. Here, we will give an overview of plant-derived compounds displaying anticancer properties that interfere with the epigenetic machinery.
Seidel, C.,Schnekenburger, M.,Mazumder, A.,Teiten, M.H.,Kirsch, G.,Dicato, M.,Diederich, M. Pergamon Press 2016 Biochemical pharmacology Vol.99 No.-
<P>Histone deacetylase (HDAC)6 is a unique isoenzyme targeting specific substrates including a-tubulin and heat shock protein (HSP)90. HDAC6 is involved in protein trafficking and degradation, cell shape and migration. Deregulation of HDAC6 activity is associated with a variety of diseases including cancer leading to a growing interest for developing HDAC6 inhibitors. Here, we identified two new structurally related 4-hydroxybenzoic acids as selective HDAC6 inhibitors reducing proliferation, colony and spheroid formation as well as viability of prostate cancer cells. Both compounds strongly enhanced alpha-tubulin acetylation leading to remodeling of microtubular organization. Furthermore, 4-hydroxybenzoic acids decreased HSP90 alpha regulation of the human androgen receptor in prostate cancer cells by increasing HSP90 alpha acetylation levels. Collectively, our data support the potential of 4-hydroxybenzoic acid derivatives as HDAC6-specific inhibitors with anti-cancer properties. (C) 2015 Elsevier Inc. All rights reserved.</P>
Histone deacetylase 6 in health and disease.
Seidel, Carole,Schnekenburger, Michael,Dicato, Mario,Diederich, Marc Future Medicine 2015 Epigenomics Vol.7 No.1
<P>Histone deacetylase (HDAC)6 is a member of the class IIb HDAC family. This enzyme is zinc-dependent and mainly localized in the cytoplasm. HDAC6 is a unique isoenzyme with two functional catalytic domains and specific physiological roles. Indeed, HDAC6 deacetylates various substrates including 관-tubulin and HSP90관, and is involved in protein trafficking and degradation, cell shape and migration. Consequently, deregulation of HDAC6 activity was associated to a variety of diseases including cancer, neurodegenerative diseases and pathological autoimmune response. Therefore, HDAC6 represents an interesting potential therapeutic target. In this review, we discuss structural features of this histone deacetylase, regulation of its expression and activity, biological functions, implication in human disease initiation and progression. Finally will describe novel and selective HDAC6 inhibitors.</P>
Anti-cancer effects of naturally derived compounds targeting histone deacetylase 6-related pathways
Lernoux, Manon,Schnekenburger, Michael,Dicato, Mario,Diederich, Marc Elsevier 2018 PHARMACOLOGICAL RESEARCH Vol.129 No.-
<P><B>Abstract</B></P> <P>Alterations of the epigenetic machinery, affecting multiple biological functions, represent a major hallmark enabling the development of tumors. Among epigenetic regulatory proteins, histone deacetylase (HDAC)6 has emerged as an interesting potential therapeutic target towards a variety of diseases including cancer. Accordingly, this isoenzyme regulates many vital cellular regulatory processes and pathways essential to physiological homeostasis, as well as tumor multistep transformation involving initiation, promotion, progression and metastasis. In this review, we will consequently discuss the critical implications of HDAC6 in distinct mechanisms relevant to physiological and cancerous conditions, as well as the anticancer properties of synthetic, natural and natural-derived compounds through the modulation of HDAC6-related pathways.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Valente, Sergio,Liu, Yiwei,Schnekenburger, Michael,Zwergel, Clemens,Cosconati, Sandro,Gros, Christina,Tardugno, Maria,Labella, Donatella,Florean, Cristina,Minden, Steven,Hashimoto, Hideharu,Chang, Yan American Chemical Society 2014 Journal of medicinal chemistry Vol.57 No.3
<P/><P>DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound <B>5</B> as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound <B>5</B> was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, <B>5</B> inhibited cell growth, whereas related compound <B>2</B> showed high cell differentiation. To the best of our knowledge, <B>2</B> and <B>5</B> are the first non-nucleoside DNMTi tested in a cancer stem cell line.</P>
Protein Kinase and HDAC Inhibitors from the Endophytic Fungus <i>Epicoccum nigrum</i>
El Amrani, Mustapha,Lai, Daowan,Debbab, Abdessamad,Aly, Amal H.,Siems, Karsten,Seidel, Carole,Schnekenburger, Michael,Gaigneaux, Anthoula,Diederich, Marc,Feger, Daniel,Lin, Wenhan,Proksch, Peter American Chemical Society and American Society of 2014 Journal of natural products Vol.77 No.1
<P>A chemical investigation of the endophytic fungus <I>Epicoccum nigrum</I> isolated from leaves of <I>Mentha suaveolens</I> collected in Morocco resulted in the isolation of five new polyketides, epicocconigrones A and B (<B>1</B> and <B>2</B>), 3-methoxyepicoccone B (<B>3</B>), 3-methoxyepicoccone (<B>4</B>), and 2,3,4-trihydroxy-6-(methoxymethyl)-5-methylbenzaldehyde (<B>5</B>), together with five known compounds (<B>6</B>–<B>10</B>). The structures of the new compounds were unambiguously determined by extensive analysis of the 1D and 2D NMR and mass spectroscopic data. Compounds <B>1</B> and <B>10</B> showed potent inhibition of at least 15 protein kinases with IC<SUB>50</SUB> values ranging from 0.07 to 9.00 μM. Moreover, compounds <B>1</B> and <B>10</B> inhibited histone deacetylase (HDAC) activities with IC<SUB>50</SUB> values of 9.8 and 14.2 μM, respectively. A preliminary structure–activity relationship is discussed. Interestingly, compounds <B>1</B> and <B>10</B> exert mainly cytostatic effects in human lymphoma RAJI and U-937 cell lines.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jnprdf/2014/jnprdf.2014.77.issue-1/np4005745/production/images/medium/np-2013-005745_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/np4005745'>ACS Electronic Supporting Info</A></P>
Ji, Seungwon,Lee, Jin-Young,Schrö,r, Jan,Mazumder, Aloran,Jang, Dong Man,Chateauvieux, Sé,bastien,Schnekenburger, Michael,Hong, Che Ry,Christov, Christo,Kang, Hyoung Jin,Lee, Youngjo,Han, By Elsevier 2018 Cancer letters Vol.416 No.-
<P><B>Abstract</B></P> <P>Stemphol (STP) is a novel druggable phytotoxin triggering mixed apoptotic and non-apoptotic necrotic-like cell death in human acute myeloid leukemia (AML). Use of several chemical inhibitors highlighted that STP-induced non-canonical programmed cell death was Ca<SUP>2+</SUP>-dependent but independent of caspases, poly (ADP-ribose) polymerase-1, cathepsin, or calpains. Similar to thapsigargin, STP led to increased cytosolic Ca<SUP>2+</SUP> levels and computational docking confirmed binding of STP within the thapsigargin binding pocket of the sarco/endoplasmic reticulum (ER) Ca<SUP>2+</SUP>-ATPase (SERCA). Moreover, the inositol 1,4,5-trisphosphate receptor is implicated in STP-modulated cytosolic Ca<SUP>2+</SUP> accumulation leading to ER stress and mitochondrial swelling associated with collapsed cristae as observed by electron microscopy. Confocal fluorescent microscopy allowed identifying mitochondrial Ca<SUP>2+</SUP> overload as initiator of STP-induced cell death insensitive to necrostatin-1 or cycloheximide. Finally, we observed that STP-induced necrosis is dependent of mitochondrial permeability transition pore (mPTP) opening. Importantly, the translational immunogenic potential of STP was validated by HMGB1 release of STP-treated AML patient cells. STP reduced colony and <I>in vivo</I> tumor forming potential and impaired the development of AML patient-derived xenografts in zebrafish.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Stemphol induces cell death by disrupting calcium homeostasis. </LI> <LI> Stemphol induces necrosis by mediating mPTP opening. </LI> <LI> Stemphol triggers immunogenic cell death markers ER stress and HMGB1 release. </LI> <LI> Stemphol impairs development of leukemia patient-derived zebrafish xenografts. </LI> </UL> </P>