- Histone Deacetylase 2 (HDAC2) Inhibitors Containing Boron
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Histone deacetylase enzymes (HDACs) are responsible for the global silencing of tumour-suppressor genes. Treatment with a histone deacetylase inhibitor (HDACi) can reverse this process and restore normal cell function. Herein, we report a small series of boron-based (boronic acid, boronate ester and closo-1,2-carborane) HDAC2 inhibitors with IC50 values in the nanomolar range. The boronate ester 4 b was the most potent compound assessed in this study (IC50=40.6±1.5 nM), followed closely by the 1,2-closo-carborane (IC50=42.9±1.5 nM). Compound 4 b exceeds the potency of the related gold-standard HDAC pan-inhibitor vorinostat (1) toward this particular HDAC isoform.
- Kavianpour, Poya,Gemmell, Madeleine C. M.,Kahlert, Jan U.,Rendina, Louis M.
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- Hypoxia-activated pro-drugs of the KDAC inhibitor vorinostat (SAHA)
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Hypoxia (lower than normal oxygen) is a characteristic of most solid tumours that results in poor cancer patient prognosis. The difference in cellular environment between normoxia (21percent oxygen) or physoxia (4–7.5percent oxygen) and hypoxia (2.0percent oxygen) causes increased resistance to radio- and chemotherapy, but also provides the opportunity to selectively release hypoxia-activated pro-drugs. This approach potentially allows targeting of chemotherapies, including lysine deacetylase (KDAC) inhibitors, to the hypoxic fraction of cells. Here, we report initial work on the development of KDAC inhibitors that are selectively released in hypoxic conditions. We have shown that the addition of a 4-nitrobenzyl (NB) or 1-methyl-2-nitroimidazole (NI) bioreductive group onto the hydroxamic acid moiety of SAHA, giving NB-SAHA and NI-SAHA, abolishes KDAC inhibition activity. Both NB-SAHA and NI-SAHA undergo enzyme-mediated bioreduction, in a hypoxia-dependent manner, to release SAHA selectively in 0.1percent oxygen. This work provides an important foundation for further investigations into the targeted release of KDAC inhibitors in hypoxic tumours.
- Calder, Ewen D. D.,Conway, Stuart J.,Folkes, Lisa K.,Hammond, Ester M.,Mistry, Ishna N.,Skwarska, Anna,Sneddon, Deborah
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- Perfluorinated HDAC inhibitors as selective anticancer agents
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A series of potent histone deacetylase inhibitors is presented that incorporate alkyl or perfluorinated alkyl chains. Several new compounds show greater in vitro antiproliferative activity than the clinically approved inhibitor, SAHA. Furthermore, the new
- Walton, James W.,Cross, Jasmine M.,Riedel, Tina,Dyson, Paul J.
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- Process Development of the Soft Histone Deacetylate Enzyme Inhibitor SHP-141: Acylation of Methyl Paraben and Suberyl Hydroxamic Acid Formation
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SHP-141 (1) is a hydroxamic acid-based inhibitor of histone deacetylase enzymes which is under development for the treatment of cutaneous T-cell lymphoma. The original synthesis of 1 involved five synthetic steps beginning with suberic acid monomethyl ester. Final deprotection of the O-benzyl hydroxamate moiety using hydrogen and palladium catalyst mandated the use of metal scavengers to reduce palladium levels to within International Council for Harmonisation (ICH) guidance. Owing to the sensitivity of 1 toward self-condensation and the potential for N-O bond cleavage under hydrogenolytic conditions, we developed an alternative route to 1 which avoids Pd-mediated hydrogenation and prolonged metal scavenger treatment. This two-step process employs readily available suberic acid and methyl paraben and has successfully delivered multiple kilograms of 1 for clinical use. Importantly, crude 1 was stabilized for recrystallization in acetonitrile (ACN) solution by the addition of 0.1% citric acid and 4% water. Additionally, the filtration and drying of suitably sized aggregates of 1 with high purity (100 area%) was accomplished via temperature cycling of the 1/ACN solution.
- Deng, Yijun,Ng Dimarco, Christina,Vakhilt, Tanya,Jonas, Marco,White, Jaclyn,Arefyev, Dennis,Tokala, Ramachandar,Akhtar, Parveen,Zhu, Lei,Sun, Xufeng,Haimowitz, Thomas,Condon, Stephen M.
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Read Online
- Synthesis, Biological Evaluation, and Computer-Aided Drug Designing of New Derivatives of Hyperactive Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitors
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The synthesis and biological evaluation of a novel series of compounds based on suberoylanilide hydroxamic acid (SAHA) had been designed as potential histone deacetylase inhibitors (HDACis). Molecular docking studies indicated that our derivatives had better fitting in the binding sites of HDAC8 than SAHA. Compounds 1-5 were synthesized through the synthetic routes. In biological test, compounds also showed good inhibitory activity in HDAC enzyme assay and more potent growth inhibition in human glioma cell lines (MGR2, U251, and U373). A representative compound, N3F, exhibited better inhibitory effect (HDAC, IC50 = 0.1187 μm; U251, IC50 = 0.8949 μm) and lower toxicity for human normal cells (LO2, IC50 = 172.5 μm and MRC5, IC50 = 213.6 μm) compared with SAHA (HDAC, IC50 = 0.8717 μm; U251, IC50 = 8.938 μm; LO2, IC50 = 86.52 μm and MRC5, IC50 = 81.02 μm). In addition, N3F obviously increased Beclin-1 and Caspase-3 and 9 as well as inhibited Bcl-2 in U251 cells. All of our results indicated that these SAHA cap derivatives could serve as potential lead compounds for further optimization. In addition, N3F and N2E both displayed promising profile as antitumor candidates for the treatment of human glioma.
- Zhang, Song,Huang, Weibin,Li, Xiaonan,Yang, Zhicheng,Feng, Binghong
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- Novel Bioactive Hybrid Compound Dual Targeting Estrogen Receptor and Histone Deacetylase for the Treatment of Breast Cancer
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A strategy to develop chemotherapeutic agents by combining several active groups into a single molecule as a conjugate that can modulate multiple cellular pathways may produce compounds having higher efficacy compared to that of single-target drugs. In th
- Tang, Chu,Li, Changhao,Zhang, Silong,Hu, Zhiye,Wu, Jun,Dong, Chune,Huang, Jian,Zhou, Hai-Bing
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Read Online
- Molecular umbrella as a nanocarrier for antifungals
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A molecular umbrella composed of two O‐sulfated cholic acid residues was applied for the construction of conjugates with cispentacin, containing a “trimethyl lock” (TML) or o‐dithiobenzylcarbamoyl moiety as a cleavable linker. Three out of five conjugates
- Skwarecki, Andrzej S.,Martynow, Dorota,Milewska, Maria J.,Milewski, S?awomir
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- Design, synthesis, and biological evaluation of HDAC degraders with CRBN E3 ligase ligands
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Histone deacetylases (HDACs) play important roles in cell growth, cell differentiation, cell apoptosis, and many other cellular processes. The inhibition of different classes of HDACs has been shown to be closely related to the therapy of cancers and other diseases. In this study, a series of novel CRBN-recruiting HDAC PROTACs were designed and synthesized by linking hydroxamic acid and benzamide with lenalidomide, pomalidomide, and CC-220 through linkers of different lengths and types. One of these PROTACs, denoted 21a, with a new benzyl alcohol linker, exhibited comparably excellent HDAC inhibition activity on different HDAC classes, acceptable degradative activity, and even better in vitro anti-proliferative activities on the MM.1S cell line compared with SAHA. Moreover, we report for the first time the benzyl alcohol linker, which could also offer the potential to be used to develop more types of potent PROTACs for targeting more proteins of interest (POI).
- Li, Jia,Lu, Wei,Lu, Yingxin,Shao, Yingying,Su, Mingbo,Sun, Danwen,Xiao, Donghuai,Zhou, Yubo,Zhu, Shulei
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- Unified Total Synthesis of Five Bufadienolides
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We report a unified total synthesis of five bufadienolides: bufalin (1), bufogenin B (2), bufotalin (3), vulgarobufotoxin (4), and 3-(N-succinyl argininyl) bufotalin (5). After the steroidal ABCD ring 8 was produced, the D ring was cross-coupled with a 2-pyrone moiety and stereoselectively epoxidized to generate 6. TMSOTf promoted a stereospecific 1,2-hydride shift from 6 to establish the β-oriented 2-pyrone of 19. Functional group manipulations from 19 furnished 1-5, which potently inhibited cancer cell growth.
- Hagiwara, Koichi,Inoue, Masayuki,Itoh, Hiroaki,Shimizu, Shinsuke
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supporting information
(2020/11/13)
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- Compound and pharmaceutical application thereof
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The invention discloses a compound and a pharmaceutical application thereof. The compound can be used as a corresponding inhibitor or a drug for treating disease through UHRF1 and HDAC double-targeting small chemical molecules or pharmaceutically acceptable salts of the small chemical molecules, so that the compound can be used for treating myelodysplastic syndrome, psoriasis, scar hyperplasia, prostate or mammary gland hyperplasia, blood tumors and solid cancers alone or in combination with other methods. The treatment effect is quite good.
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Paragraph 0019; 0021
(2018/12/13)
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- Preparation method of intermediate suberic anhydride of vorinostat
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The invention discloses a preparation method of an intermediate suberic anhydride of vorinostat. The preparation method comprises the following steps of A, adding certain amounts of suberic acid and acetic anhydride into a multi-mouth flask respectively, and placing the flask into a heat collection type constant temperature heating magnetic agitator; B, controlling certain heating temperature and reaction time, wherein the heat collection type constant temperature heating magnetic agitator is provided with reduced pressure distillation at the same time; C, carrying out the reduced pressure distillation while a reaction is carried out in a reaction process, shifting out acetic acid, which is one of products, regulating pressure, continuously carrying out the reaction, carrying out in-situ pressure reduction at a later period of the reaction, and distilling and removing the unreacted acetic anhydride; D, after the reaction is terminated, directly adding a devitrifying solvent into a reaction bulb, carrying out cooling and crystallization, and carrying out suction filtration, washing and vacuum drying, so as to obtain white solid suberic anhydride. The method is easy and feasible, and is simple and convenient to operate; the progress of a positive reaction is greatly accelerated; the unreacted acetic anhydride is duly removed through the reduced pressure distillation in the reaction process; the process of the post treatment is simplified; moreover, the devitrifying solvent is directly added after the reaction is terminated; a high-purity target product suberic anhydride is obtained.
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Paragraph 0026; 0027; 0028; 0029; 0030; 0031; 0032-0059
(2017/08/29)
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- Preparation method of 8-furan-8-oxo methyl caprylate
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The invention relates to a preparation method of 8-furan-8-oxo methyl caprylate. The method comprises the steps of adding suberic acid and acetic anhydride into a reaction bottle, after complete heating reaction, carrying out vacuum distillation to remove a solvent and a by-product to obtain cyclooctyl dicarboxylic anhydride; reacting cyclooctyl dicarboxylic anhydride with furan under the presence of a catalyst, after reaction is completed, filtering suberic acid, carrying out spin drying on an organic solvent and adding an alkaline solution to fully dissolve solid; adding the solvent to extract and purify, acidifying an aqueous phase and extracting 8-furan-8-oxooctanoic acid; and finally carrying out methanol esterification to obtain 8-furan-8-oxo methyl caprylate. The synthetic route of a target product is simplified, the total yield is improved and use of an environmentally unfriendly reagent is avoided. The method has the advantages of being low in cost, relatively high in yield, simple to operate and suitable for indusial production.
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Paragraph 0018
(2017/07/11)
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- Oxygen bridge bis-heptylene sulfonamide compound containing suberic acid monoanilide group as well as synthesizing method, application and anti-breast cancer drug composition of oxygen bridge bis-heptylene sulfonamide compound
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The invention belongs to technical field of medicines and specifically relates to an oxygen bridge bis-heptylene sulfonamide compound containing a suberic acid monoanilide group as well as a synthesizing method, application and an anti-breast cancer drug composition of the oxygen bridge bis-heptylene sulfonamide compound. The oxygen bridge bis-heptylene sulfonamide compound containing the suberic acid monoanilide group is prepared by one-step reaction of the following raw materials: 3-(4-hydroxyphenyl)-4-suberic acid monoanilino-furan and an ethenyl sulfonamide derivative at the temperature of 90 DEG C for 3 without a solvent or a catalyst. The oxygen bridge bis-heptylene sulfonamide compound is different from the existing anti-breast cancer drug tamoxifen in action modes and is an anti-breast cancer compound acting on an estrogen receptor and histone histone deacetylase dual target sites.
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Paragraph 0078; 0080; 0081
(2017/09/02)
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- 4-Biphenylalanine- and 3-Phenyltyrosine-Derived Hydroxamic Acids as Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A
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Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50value of 25.4 μm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell-permeable derivatives clearly showed a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells.
- Morera, Ludovica,Roatsch, Martin,Fürst, Michael C. D.,Hoffmann, Inga,Senger, Johanna,Hau, Mirjam,Franz, Henriette,Schüle, Roland,Heinrich, Markus R.,Jung, Manfred
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p. 2063 - 2083
(2016/10/22)
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- Structural Requirements of Histone Deacetylase Inhibitors: SAHA Analogs Modified on the Hydroxamic Acid
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Histone deacetylase (HDAC) proteins have emerged as targets for anti-cancer therapeutics, with several inhibitors used in the clinic, including suberoylanilide hydroxamic acid (SAHA, vorinostat). Because SAHA and many other inhibitors target all or most o
- Bieliauskas, Anton V.,Weerasinghe, Sujith V.W.,Negmeldin, Ahmed T.,Pflum, Mary Kay H.
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p. 373 - 382
(2016/05/19)
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- Synthesis and structure-activity relationships of novel hybrid ferrocenyl compounds based on a bicyclic core skeleton for breast cancer therapy
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Breast cancer is the most frequent cancer in women worldwide, and incidence is increasing year by year. Although current selective estrogen receptor modulators (SERMs) have clear advantages in the treatment of hormone-responsive breast cancer, they are ineffective for ER(-). In this study, we describe the design and synthesis of a series of dual-acting estrogen receptor (ER) and histone deacetylase (HDAC) inhibitors with incorporation of the ferrocenyl moiety, leading to novel hybrid ferrocenyl complexes (FcOBHS-HDACis) for breast cancer therapy. It is worth to note that these ferrocenyl conjugates could not only potently inhibit HDACs and the proliferation of ERα positive (ER(+)) breast cancer cells (MCF-7), but also show significant antiproliferative effect on ER(-) breast cancer cells (MDA-MB-231). Thus, the FcOBHS-HDACi conjugates represent a novel approach to the development of efficiently dual-acting agents for treatment of breast cancer.
- Li, Changhao,Tang, Chu,Hu, Zhiye,Zhao, Chenxi,Li, Chenlu,Zhang, Silong,Dong, Chune,Zhou, Hai-Bing,Huang, Jian
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p. 3062 - 3074
(2016/06/13)
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- A oxo bridge Shuanghuan -[ 2.2.1]- heptylene class compound and use thereof
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The invention belongs to the technical field of medicines, and particularly discloses an oxygen-bridge bicyclo-[2.2.1]-heptylene compound comprising N-hydroxy-N'-phenyloctanediamide (SAHA) or a like structure, wherein the oxygen-bridge bicyclo-[2.2.1]-heptylene compound has an activity of resisting breast cancer. 3-(4-hydroxy penyl)-4-octanedioic acid monoanilide-furan and a vinyl sulphonate derivative are taken as raw materials and are reacted without a solvent or a catalyst at the temperature of 90 DEG C for 3 hours to further prepare the oxygen-bridge bicyclo-[2.2.1]-heptylene compound comprising the octanedioic acid monoanilide, and then the compound is reacted with oxammonium hydrochloride to obtain the oxygen-bridge bicyclo-[2.2.1]-heptylene compound comprising the N-hydroxy-N'-phenyloctanediamide. The experiments in vitro show that the oxygen-bridge bicyclo-[2.2.1]-heptylene compound has a great inhibitory activity on an MCF-7 cell in comparison to an existing anti-breast-cancer medicine tamoxifen.
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Paragraph 0049-0051
(2016/12/01)
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- NOVEL COMPOUNDS SUPPORTS HEMATOPOIETIC STEM CELLS AND RED BLOOD CELLS
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The present disclosure relates to methods of using a compound to induce regeneration of hematopoietic stem cells or increase the recovery of red blood cells. In some aspects, the present methods can be used to with or in place of erythropoietin in patients to mitigate the side effects of erythropoietin.
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Page/Page column 51
(2015/12/17)
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- Synthesis and biological evaluation of aziridin-1-yl oxime-based vorinostat analogs as anticancer agents
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The suberoyl anilide hydroxamic acid (vorinostat) analogs with the aziridin-1-yl oxime moiety as a possible metal chelating functionality have been synthesized. Their biological activity and stability under physiological conditions have been evaluated. Although some of the synthesized compounds demonstrated high antiproliferative activity against human HT1080 fibrosarcoma (HT1080, IC50 0.3-7.7 μM) comparable to vorinostat (HT1080, IC50 2.4 μM), they showed only weak histone deacetylase inhibition activity in HeLa cell line extracts.
- Nikitjuka, Anna,Shestakova, Irina,Romanchikova, Nadezhda,Jirgensons, Aigars
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p. 647 - 657
(2016/01/15)
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- Cap-modified hydroxamate analogues as histone deacetylases inhibitors and antitumor agents
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Two series of SAHA-liked hydroxamate analogues were designed, synthesized and evaluated for their biological activities against nuclear HDACs. Compounds of Series I were found to be very effective inhibitors of cancer cell growth in the PC-3, Hut78, K562
- Zhang, Qing-Wei,Feng, Juan,Li, Jian-Qi
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p. 129 - 134
(2014/02/14)
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- Efficient new constructs against triple negative breast cancer cells: Synthesis and preliminary biological study of ferrocifen-SAHA hybrids and related species
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Chemotherapeutic agents combining several active groups within a single molecule can modulate multiple cellular pathways and, thus, exhibit higher efficacy than single-target drugs. In this study, six new hybrid compounds combining tamoxifen (TAM) or ferrocifen (FcTAM) structural motifs with suberoylanilide hydroxamic acid (SAHA) were synthesised and evaluated. Antiproliferative activity was first explored in cancer cell lines. Combining FcTAM and SAHA structural motifs to form the unprecedented FcTAM-SAHA hybrid molecule led to an increased cytotoxicity (IC50 = 0.7 μM) in triple-negative MDA-MB-231 breast cancer cells when compared to FcTAM or SAHA alone (IC50 = 2.6 μM and 3.6 μM, respectively), while the organic hybrid analogue TAM-SAHA was far less cytotoxic (IC50 = 8.6 μM). In hormone-dependent MCF-7 breast cancer cells, FcTAM-SAHA was more active (IC50 = 2.0 μM) than FcTAM (IC50 = 4.4 μM) and TAM-SAHA (IC50 > 10 μM), but less toxic than SAHA (IC 50 = 1.0 μM). Surprisingly, FcTAM-PSA, an N1- phenylsuberamide derivative, also possessed strong antiproliferative activity (IC50 = 0.5 μM and 1.8 μM in MDA-MB-231 and MCF-7 cells, respectively). Subsequent biochemical studies indicate that estrogen receptor alpha (ERα) and histone deacetylases (HDAC) are not the main targets of the hybrid compounds for their antiproliferative effect. Interestingly, both organometallic compounds were able to induce p21waf1/cip1 gene expression in MCF-7 breast cancer cells in accordance with their antiproliferative activity.
- Cazares Marinero, Jose De Jesus,Lapierre, Marion,Cavailles, Vincent,Saint-Fort, Renette,Vessieres, Anne,Top, Siden,Jaouen, Gerard
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p. 15489 - 15501
(2013/11/06)
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- Biological and biophysical properties of the histone deacetylase inhibitor suberoylanilide hydroxamic acid are affected by the presence of short alkyl groups on the phenyl ring
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Inhibition of histone deacetylases (HDACs) leads to growth arrest, differentiation, or apoptosis of tumor cell lines, suggesting HDACs as promising targets for cancer therapy. At present, only one HDAC inhibitor (HDACi) is used in therapy: suberoylanilide hydroxamic acid (SAHA). Here, we describe the synthesis and biological evaluation of a new series of compounds derived from SAHA by substituting short alkyl chains at various positions of the phenyl ring. Such modifications induced variable effects ranging from partial loss of activity to increased potency. Through molecular modeling, we describe a possible interaction between HDAC7 proline 809, a residue that is strictly conserved within class 2 enzymes only, and the amide group of HDACi, while nuclear magnetic resonance experiments indicated that dimethyl m-substitution may stabilize the inhibitor in the active site. Our data provide novel information on the structure - activity relationship of HDACi and suggest new ways for developing second generation SAHA-like molecules.
- Oger, Frédérik,Lecorgne, Aurélien,Sala, Elisa,Nardese, Vanessa,Demay, Florence,Chevance, Soizic,Desravines, Danielle C.,Aleksandrova, Nataliia,Guével, Rémy Le,Lorenzi, Simone,Beccari, Andrea R.,Barath, Peter,Hart, Darren J.,Bondon, Arnaud,Carettoni, Daniele,Simonneaux, Gérard,Salbert, Gilles
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experimental part
p. 1937 - 1950
(2010/07/17)
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- New aryldithiolethione derivatives as potent histone deacetylase inhibitors
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A series of dithiolethione derivatives was synthesized and the in vitro HDAC inhibitory activity was tested. The most active compounds, 1 and 2, exhibited an IC50 in nM range with a strong hyperacetylation of histone H4 in A549 cells. The HDAC
- Tazzari, Valerio,Cappelletti, Graziella,Casagrande, Manolo,Perrino, Elena,Renzi, Luigi,Del Soldato, Piero,Sparatore, Anna
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scheme or table
p. 4187 - 4194
(2010/09/12)
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- Trithiocarbonates-Exploration of a new head group for HDAC inhibitors
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Inhibition of histone deacetylases class I/II enzymes is a new, promising approach for cancer therapy. In the present study, we disclose a new structural class of HDAC inhibitors with the trithiocarbonate motif. A clear structure-activity-relationship was obtained for the cap-linker motif and the putative Zn2+ complexing head group. Selected analogs display potent inhibition of HDAC enzymatic activity and a cellular potency comparable to that of suberoylanilide hydroxamic acid (SAHA), recently approved for treatment of patients with advanced cutaneous T-cell lymphoma.
- Dehmel, Florian,Ciossek, Thomas,Maier, Thomas,Weinbrenner, Steffen,Schmidt, Beate,Zoche, Martin,Beckers, Thomas
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p. 4746 - 4752
(2008/12/21)
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- HISTONE DEACETYLASE INHIBITORS AS THERAPEUTICS FOR NEUROLOGICAL DISEASES
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The invention provides HDAC inhibitors that may be used as therapeutics for the treatment of a neurodegenerative or neuromuscular condition. The invention provides compounds of formula I. The invention also provides pharmaceutical compositions and articles of manufacture that include these compounds, as well as methods of treating and methods of preventing or delaying the onset of a neurodegenerative or neuromuscular condition.
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Page/Page column 40; 41
(2008/06/13)
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- Tricyclic hydroxamate and benzaminde derivatives, compositions and methods
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The present invention relates to compounds and methods for inhibiting histone deacetylase enzymatic activity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit histone deacetylases (HDACs), and in the treatment of conditions mediated by HDAC, cancer, proliferative conditions, psoriasis, and also central nervous system diseases. It further deals with processes for preparing said compounds.
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Page/Page column 11; 36
(2008/06/13)
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