- Platinum(IV) prodrugs multiply targeting genomic DNA, histone deacetylases and PARP-1
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Several Pt(IV) prodrugs containing SAA, a histone deacetylases inhibitor, were designed and prepared for multiply targeting genomic DNA, histone deacetylases and PARP-1. The resulting Pt(IV) prodrug had significantly strong antiproliferative activity against the tested cancer cell lines, especially SAA1, derived from the conjugation of cisplatin and SAA, had potent ability to overcome cisplatin resistance. Under the combined action of DNA platination and inhibition of HDACs and PARP-1 activity, the cytotoxic activity of SAA1 was 174-fold higher than cisplatin against cisplatin-resistant SGC7901/CDDP cancer cells. The mechanism of action of SAA1 was preliminarily investigated, in which cellular uptake, cell apoptosis and cell cycle arrest as well as western blot analysis were made by treating SAA1 with SGC7901/CDDP cells. Besides, HDACs inhibition activity and PARP-1 enzyme inhibition of SAA1 were also studied.
- Xu, Zichen,Hu, Weiwei,Wang, Zhimei,Gou, Shaohua
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Read Online
- 2-Hydroxypropyl-β-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease
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Niemann-Pick type C1 (NPC1) disease is a fatal neurovisceral disease for which there are no FDA approved treatments, though cyclodextrin (HPβCD) slows disease progression in preclinical models and in an early phase clinical trial. Our goal was to evaluate the mechanism of action of a previously described combination-therapy, Triple Combination Formulation (TCF) – comprised of the histone deacetylase inhibitor (HDACi) vorinostat/HPβCD/PEG – shown to prolong survival in Npc1 mice. In these studies, TCF's benefit was attributed to enhanced vorinostat pharmacokinetics (PK). Here, we show that TCF reduced lipid storage, extended lifespan, and preserved neurological function in Npc1 mice. Unexpectedly, substitution of an inactive analog for vorinostat in TCF revealed similar efficacy. We demonstrate that the efficacy of TCF was attributable to enhanced HPβCD PK and independent of NPC1 protein expression. We conclude that although HDACi effectively reduce cholesterol storage in NPC1-deficient cells, HDACi are ineffective in vivo in Npc1 mice.
- Davidson, Jessica,Molitor, Elizabeth,Moores, Samantha,Gale, Sarah E.,Subramanian, Kanagaraj,Jiang, Xuntian,Sidhu, Rohini,Kell, Pamela,Zhang,Fujiwara, Hideji,Davidson, Cristin,Helquist, Paul,Melancon, Bruce J.,Grigalunas, Michael,Liu, Gang,Salahi, Farbod,Wiest, Olaf,Xu, Xin,Porter, Forbes D.,Pipalia, Nina H.,Cruz, Dana L.,Holson, Edward B.,Schaffer, Jean E.,Walkley, Steven U.,Maxfield, Frederick R.,Ory, Daniel S.
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Read Online
- 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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p. 2786 - 2791
(2020/06/25)
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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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supporting information
(2020/04/24)
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- The involvement of the mitochondrial amidoxime reducing component (MARC) in the reductive metabolism of hydroxamic acidsS
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The mitochondrial amidoxime reducing component is a recently discovered molybdenum enzyme in mammals which, in concert with the electron transport proteins cytochrome b5 and NADH cytochrome b5 reductase, catalyzes the reduction of N-oxygenated structures.
- Ginsel, Carsten,Plitzko, Birte,Froriep, Danilo,Stolfa, Diana A.,Jung, Manfred,Kubitza, Christian,Scheidig, Axel J.,Havemeyer, Antje,Clement, Bernd
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p. 1396 - 1402
(2018/09/13)
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- An Endogenous Reactive Oxygen Species (ROS)-Activated Histone Deacetylase Inhibitor Prodrug for Cancer Chemotherapy
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Suberoylanilide hydroxamic acid (SAHA, vorinostat) is a potent small-molecule pan-inhibitor of histone deacetylases (HDACs) approved for treatment of cutaneous T-cell lymphoma (CTCL). However, SAHA exhibits poor selectivity for cancer cells over noncancer cells. With an aim to improving its selectivity for cancer cells, we generated a novel SAHA prodrug (SAHA-OBP) that is activated in the presence of hydrogen peroxide, a reactive oxygen species (ROS) known to be overexpressed in cancer cells. The high endogenous ROS content in cancer cells triggers rapid removal of the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl carbonyl (OBP) cap to release active SAHA. The SAHA-OBP prodrug demonstrates selective activity against multiple cancer cell lines such as HeLa, MCF-7, MDA-MB-231, and B16-F10, while remaining benign toward noncancer cells. The downstream effects of SAHA released from SAHA-OBP in cancer cells is the induction of apoptosis. SAHA-OBP was also found to be effective on multicellular tumor spheroids (MCTS). The SAHA prodrug designed in this study undergoes rapid ROS-dependent activation and imparts much-needed selectivity to SAHA for cancer cells.
- Bhagat, Somnath D.,Singh, Usha,Mishra, Ram Kumar,Srivastava, Aasheesh
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supporting information
p. 2073 - 2079
(2018/09/06)
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- H2O2/Peroxynitrite-Activated Hydroxamic Acid HDAC Inhibitor Prodrugs Show Antileukemic Activities against AML Cells
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Occurrence of acute myeloid leukemia (AML) results in abundant endogenous reactive oxygen species (ROS)/reactive nitrogen species (RNS) in AML cells and in disease-relevant microenvironments. Histone deacetylase inhibitor (HDACi) prodrug approach was designed accordingly by masking the hydroxamic acid zinc binding group with hydrogen peroxide (H2O2)/peroxynitrite (PNT)-sensitive, self-immolative aryl boronic acid moiety. Model prodrugs 5-82 and 5-23 were activated in AML cells to release cytotoxic HDACis, evidenced by inducing acetylation markers and reducing viability of AML cells. Intracellular activation and antileukemic activities of prodrug were increased or decreased by ROS/PNT inducers and scavengers, respectively. Prodrugs 5-82 and 5-23 also enhanced the potency of chemotherapy drug cytarabine, supporting the potentials of this prodrug class in combinatorial treatment.
- Liao, Yi,Xu, Liping,Ou, Siyu,Edwards, Holly,Luedtke, Daniel,Ge, Yubin,Qin, Zhihui
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p. 635 - 640
(2018/06/22)
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- Metal-Free Synthesis of N-Aryl Amides using Organocatalytic Ring-Opening Aminolysis of Lactones
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Catalytic ring-opening of bio-sourced non-strained lactones with aromatic amines can offer a straightforward, 100 % atom-economical, and sustainable pathway towards relevant N-aryl amide scaffolds. Herein, the first general, metal-free, and highly efficient N-aryl amide formation is reported from poorly reactive aromatic amines and non-strained lactones under mild operating conditions using an organic bicyclic guanidine catalyst. This protocol has high application potential as exemplified by the formal syntheses of drug-relevant molecules.
- Guo, Wusheng,Gómez, José Enrique,Martínez-Rodríguez, Luis,Bandeira, Nuno A. G.,Bo, Carles,Kleij, Arjan W.
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p. 1969 - 1975
(2017/05/16)
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- Photoorganocatalytic One-Pot Synthesis of Hydroxamic Acids from Aldehydes
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An efficient one-pot synthesis of hydroxamic acids from aldehydes and hydroxylamine is described. A fast, visible-light-mediated metal-free hydroacylation of dialkyl azodicarboxylates was used to develop the subsequent addition of hydroxylamine hydrochloride. A range of aliphatic and aromatic aldehydes were employed in this reaction to give hydroxamic acids in high to excellent yields. Application of the current methodology was demonstrated in the synthesis of the anticancer medicine vorinostat.
- Papadopoulos, Giorgos N.,Kokotos, Christoforos G.
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supporting information
p. 6964 - 6967
(2016/05/11)
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- Preparation method of anti-cancer drug vorinostat
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The invention discloses a preparation method of an anti-cancer drug vorinostat. The method comprises the following steps that 1, a hydrophilic substrate and suberic acid make contact with each other to be self-assembled to obtain a suberic acid-substrate self-assembled membrane; 2, the suberic acid-substrate self-assembled membrane makes contact with hydroxylamine hydrochloride in THF in the presence of 1,3-dicyclohexylcarbodiimide, after reacting is finished, 4M of a HCl solution is added, reacting under stirring is conducted, and dichloromethane extraction is conducted to obtain N-hydroxyl-7-carboxyl-heptamide; 3, N-hydroxyl-7-carboxyl-heptamide reacts with aniline to obtain the vorinostat in the presence of 1,3-dicyclohexylcarbodiimide and alkali. According to the preparation method of the vorinostat, a novel synthesis way of the vorinostat is provided. By means of the preparation method of the vorinostat, the conditions are mild, the selectivity is good, the reacting time, especially the aniline amidation reacting time is greatly shortened, and meanwhile the yield of the vorinostat is greatly increased.
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Paragraph 0051; 0052
(2017/06/02)
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- Method for preparing anticarcinogen vorinostat
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The invention discloses a method for preparing anticarcinogen vorinostat. The method includes: (1) subjecting suberic anhydride and aniline to contact reaction in water and 1,4-dioxane at the temperature of 5-10 DEG C in the presence of CuI, performing filtering after reaction is finished, regulating the pH of filtrate to 5-6, performing suction filtration, washing filter cake obtained after suction filtration, and drying to obtain 7-phenylcarbamoylheptanoic acid; (2) dissolving the 7-phenylcarbamoylheptanoic acid in methanol, adding cation exchange resin and ZnCl2, heating to 50-55 DEG C for reaction for 3 hours, concentrating, extracting with ethyl acetate, concentrating, washing with petroleum ether, and drying to obtain suberanilic acid methyl ester; (3) subjecting hydroxylamine hydrochloride and sodium methoxide to stirring reaction in absolute methanol for 0.5-1h, filtering prior to adding the suberanilic acid methyl ester into filtrate for reaction at the temperature of 40 DEG C for 3-5 hours, cooling to room temperature, regulating the pH to 7, performing suction filtration, washing filter cake, and performing recrystallization with ethyl alcohol to obtain the vorinostat. The method is high in yield, quick in reaction and simple to operate.
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Paragraph 0023; 0025
(2017/06/23)
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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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- Racemization free longer N-terminal peptide hydroxamate synthesis on solid support using ethyl 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate
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A facile, efficient, racemization-free, and environment friendly protocol for the synthesis of peptide hydroxamic acids directly from carboxylic/amino acids by ethyl 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate in the presence of DIPEA/DMAP at room temperature is described. The compatibility of this method with Fmoc based solid phase peptide synthesis (SPPS) is also demonstrated by synthesizing three relatively large N-terminal peptide hydroxamic acids on resin. Also, some biologically important hydroxamates are synthesized using this protocol.
- Manne, Srinivasa Rao,Thalluri, Kishore,Giri, Rajat Subhra,Paul, Ashim,Mandal, Bhubaneswar
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supporting information
p. 6108 - 6111
(2015/10/28)
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- PROCESS FOR THE PREPARATION OF VORINOSTAT
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The present invention relates to an improved process for the preparation of the active pharmaceutical ingredient vorinostat. In particular it relates to a process for preparing vorinostat substantially free from impurities, involving suberic acid, aniline and hydroxylamine as starting materials.
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Page/Page column 6-7
(2011/11/06)
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- Oxime amides as a novel zinc binding group in histone deacetylase inhibitors: Synthesis, biological activity, and computational evaluation
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Several oxime containing molecules, characterized by a SAHA-like structure, were explored to select a potentially new biasing binding element for the zinc in HDAC catalytic site. All compounds were evaluated for their in vitro inhibitory activity against the 11 human HDACs isoforms. After identification of a "hit" molecule, a programmed variation at the cap group and at the linker was carried out in order to increase HDAC inhibition and/or paralogue selectivity. Some of the new derivatives showed increased activity against a number of HDAC isoforms, even if their overall activity range is still far from the inhibition values reported for SAHA. Moreover, different from what was reported for their hydroxamic acid analogues the new α-oxime amide derivatives do not select between class I and class II HDACs; rather they target specific isoforms in each class. These somehow contradictory results were finally rationalized by a computational assisted SAR, which gave us the chance to understand how the oxime derivatives interact with the catalytic site and justify the observed activity profile.
- Botta, Cinzia B.,Cabri, Walter,Cini, Elena,De Cesare, Lucia,Fattorusso, Caterina,Giannini, Giuseppe,Persico, Marco,Petrella, Antonello,Rondinelli, Francesca,Rodriquez, Manuela,Russo, Adele,Taddei, Maurizio
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experimental part
p. 2165 - 2182
(2011/05/14)
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- IMPROVED PROCESS
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The present invention relates to an improved process for the preparation of the active pharmaceutical ingredient vorinostat. In particular it relates to a process for preparing vorinostat substantially free from impurities.
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Page/Page column 18
(2010/04/30)
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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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- NEW ANTICANCER COMPOUNDS
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The present invention relates to new polysulf urated compounds containing 2 or more sulphur atoms belonging to the class of organic thiosulf onates, or dithiole-thione derivatives cyclic or linear, or trithiocarbonates for the use alone or in combination with other anticancer treatments for the treatment and/or prevention of cancer and inflammatory diseases.
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Page/Page column 20-21
(2009/06/27)
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- NOVEL PROCESS FOR THE PREPARATION OF VORINOSTAT
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The present invention relates to an improved process for the preparation of the active pharmaceutical ingredient, vorinostat. In particular it relates to an efficient process for the preparation of vorinostat of high purity without the requirement to isolate any synthetic intermediate compounds.
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Page/Page column 12-13
(2009/10/09)
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- Efficient continuous flow synthesis of hydroxamic acids and suberoylanilide hydroxamic acid preparation
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A continuous flow tubing reactor can be used to readily transform methyl or ethyl carboxylic esters into the corresponding hydroxamic acids. Flow rate, reactor volume, and temperature were optimized for the preparation of a small collection of hydroxamic acids. Synthetic advantages were identified as an increased reaction rate and higher product purity. This method was also successfully applied to the multistep preparation of suberoylanilide hydroxamic acid, a potent HDAC inhibitor used in anticancer therapy.
- Riva, Elena,Gagliardi, Stefania,Mazzoni, Caterina,Passarella, Daniele,Rencurosi, Anna,Vigo, Daniele,Martinelli, Marisa
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supporting information; experimental part
p. 3540 - 3543
(2009/09/30)
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- PHARMACEUTICAL COMPOSITIONS OF HDAC INHIBITORS AND CHELATABLE METAL COMPOUNDS, AND METAL-HDAC INHIBITOR CHELATE COMPLEXES
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The present invention provides pharmaceutical compositions of an HDAC inhibitor and a chelatable metal compound. In one embodiment, the invention provides a method of treating cancer and alleviating the side effects of the HDAC inhibitor by administering the pharmaceutical composition. In another embodiment, the present invention also provides pharmaceutical compositions of metal HDAC inhibitor chelate complexes. In another embodiment, the invention provides methods of treating cancer by administering the pharmaceutical compositions. The invention provides crystalline compositions of metal HDAC inhibitor chelate complexes and methods of producing same.
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Page/Page column 32-33
(2008/06/13)
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- Formulations Of Suberoylanilide Hydroxamic Acid And Methods For Producing Same
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The present invention provides a pharmaceutical composition or crystalline composition with a specific dissolution profile, which comprises suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient. The present invention provides a process of producing said crystalline composition or pharmaceutical composition. The present invention also provides compositions with a specific particle size distribution.
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Page/Page column 14-15
(2008/12/05)
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- COMBINATION METHODS OF SAHA AND TARGRETIN FOR TREATING CANCER
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The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a second amount of Targretin. The
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Page/Page column 52-53
(2008/06/13)
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- Method of treating cancers with SAHA and pemetrexed
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The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a second amount of an anti-cancer agent. The HDAC inhibitor and the anti-cancer agent may be administered to comprise therapeutically effective amounts. In various aspects, the effect of the HDAC inhibitor and the anti-cancer agent may be additive or synergistic.
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Page/Page column 28-29
(2008/06/13)
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- METHODS OF USING SAHA AND ERLOTINIB FOR TREATING CANCER
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The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of a histone deacetylase (HDAC) inhibitor such as suberoylanilide hydroxamic acid (SAHA), or a pharmaceutically acceptable salt or hydrate thereof, and a second amount of one or more anti-cancer agents, including Erlotinib. The HDAC inhibitor and the anti-cancer agent may be administered to comprise therapeutically effective amounts. In various aspects, the effect of the HDAC inhibitor and the anti-cancer agent may be additive or synergistic.
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Page/Page column 58-59
(2008/06/13)
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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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- Fluorous-based small-molecule microarrays for the discovery of histone deacetylase inhibitors
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(Figure Presented) Noncovalent immobilization is an attractive method for identifying inhibitors of histone deacetylases (HDACs). Fluorous-based small-molecule microarrays were validated as an effective method. Three enzymes and three assays (microarray, biochemical activity, and surface plasmon resonance) were used to identify inhibitors of HDACs and to compare them.
- Vegas, Arturo J.,Bradner, James E.,Tang, Weiping,McPherson, Olivia M.,Greenberg, Edward F.,Koehler, Angela N.,Schreiber, Stuart L.
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p. 7960 - 7964
(2008/09/19)
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- Design and synthesis of non-hydroxamate histone deacetylase inhibitors: Identification of a selective histone acetylating agent
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A series of suberoylanilide hydroxamic acid (SAHA)-based non-hydroxamates was designed, synthesized, and evaluated for their histone deacetylase (HDAC) inhibitory activity. Among these, methyl sulfoxide 15 inhibited HDACs in enzyme assays and caused hyperacetylation of histone H4 while not inducing the accumulation of acetylated α-tubulin in HCT116 cells.
- Suzuki, Takayoshi,Matsuura, Azusa,Kouketsu, Akiyasu,Hisakawa, Shinya,Nakagawa, Hidehiko,Miyata, Naoki
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p. 4332 - 4342
(2007/10/03)
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- COMBINATION METHODS OF TREATING CANCER
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The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, in a first treatment procedure, and a second amount of an anti-cancer agent in a second treatment procedure. The first and second amounts together comprise a therapeutically effective amount. The effect of the HDAC inhibitor and the anti-cancer agent may be additive or synergistic.
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Page/Page column 82-83
(2008/06/13)
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- Identification of a potent non-hydroxamate histone deacetylase inhibitor by mechanism-based drug design
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In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, we synthesized several suberoylanilide hydroxamic acid (SAHA)-based compounds designed on the basis of the catalytic mechanism of HDACs. Among these compounds, mercaptoacetamide 5b was found to be as potent as SAHA. Kinetic enzyme assays and molecular modeling are also reported. In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, we synthesized several suberoylanilide hydroxamic acid (SAHA)-based compounds designed on the basis of the catalytic mechanism of HDACs. Among these compounds, 5b was found to be as potent as SAHA. Kinetic enzyme assays and molecular modeling suggested that the mercaptoacetamide moiety of 5b interacts with the zinc in the active site of HDACs and removes a water molecule from the reactive site of the deacetylation.
- Suzuki, Takayoshi,Matsuura, Azusa,Kouketsu, Akiyasu,Nakagawa, Hidehiko,Miyata, Naoki
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p. 331 - 335
(2007/10/03)
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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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- Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors
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Inhibitors of histone deacetylases (HDAC) are emerging as a promising class of anti-cancer agents. A mercaptoamide functionality was designed as a bidentate zinc chelator and incorporated into the hydroxamic acid based SAHA (1) scaffold in order to identify non-hydroxamate compounds as potential inhibitors of histone deacetylases. Two sets of mercaptoamides 2 and 3 with varying spacer length were synthesized and their HDAC inhibitory activity was evaluated. Low micromolar inhibition was observed for mercaptoamides 2e, 3b, and 3d.
- Anandan, Sampath-Kumar,Ward, John S.,Brokx, Richard D.,Bray, Mark R.,Patel, Dinesh V.,Xiao, Xiao-Xi
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p. 1969 - 1972
(2007/10/03)
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- Novel histone deacetylase inhibitors: Design, synthesis, enzyme inhibition, and binding mode study of SAHA-Based non-hydroxamates
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In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) were designed and synthesized as (i) substrate (acetyl lysine) analogues (compounds 3-7), (ii) analogu
- Suzuki, Takayoshi,Nagano, Yuki,Matsuura, Azusa,Kohara, Arihiro,Ninomiya, Shin-Ichi,Kohda, Kohfuku,Miyata, Naoki
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p. 4321 - 4326
(2007/10/03)
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- The Synthesis of N-Hydroxy-N'-phenyloctanediamide and Its Inhibitory Effect on Proliferation of AXC Rat Prostate Cancer Cells
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We have developed a practical synthesis of N-hydroxy-N'-phenyloctanediamide from the methyl ester of suberanilic acid.It provides the product in high yield and purity with a simple purification process.We have found that at 10-5 M it has a dramatic effect on T/5 AXC/SSh rat prostate cancer cells in vitro.It is a potent inhibitor of cell proliferation and it changes the cell morphology to resemble nonmalignant cells.
- Stowell, John C.,Huot, Rachel I.,Voast, Lainie Van
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p. 1411 - 1413
(2007/10/02)
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