- Novel SAHA analogues inhibit HDACs, induce apoptosis and modulate the expression of microRNAs in hepatocellular carcinoma
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In eukaryotes, transcriptional regulation occurs via chromatin remodeling, mainly through post translational modifications of histones that package DNA into structural units. Histone deacetylases (HDACs) are enzymes that play important role in various biological processes by repressing gene expression. Suberoylanilide hydroxamic acid (SAHA) is a known HDAC inhibitor that showed significant anti cancer activity by relieving gene silencing against hematologic and solid tumors. We have designed and synthesized a series of SAHA analogs C1–C4 and performed biological studies to elucidate its anti-cancer effects. It is observed that SAHA analogs significantly inhibited cell proliferation and induced apoptosis in hepatocellular carcinoma (HCC) cell lines HepG2 and SK-HEP-1. These analogs also showed non-toxic activity towards primary human hepatocytes, which describes its tumor specificity. SAHA analogs exhibited strong HDAC inhibition, which is 2–3 fold higher compared to SAHA. Moreover, these molecules induced hyper acetylation of histone H3 at various positions on the lysine residue. Further, it is observed that SAHA analogs are strong inducers of apoptosis, as they regulated the expression of various proteins involved in both extrinsic and intrinsic pathways. Interestingly, SAHA analogs induced upregulation of tumor suppressor miRNAs by activating its biogenesis pathway. Further, it is confirmed by microRNA (miRNA) prediction tools that these miRNAs are capable of targeting various anti-apoptotic genes. Based on these findings we conclude that SAHA analogs could be strong HDAC inhibitors with promising apoptosis inducing nature in HCC.
- Srinivas, Chatla,Swathi,Priyanka,Anjana Devi,Subba Reddy,Janaki Ramaiah,Bhadra, Utpal,Bhadra, Manika Pal
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- α,?-Didehydrosuberoylanilide hydroxamic acid (DDSAHA) as precursor and possible analogue of the anticancer drug SAHA
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An alternate synthetic route to the important anticancer drug suberoylanilide hydroxamic acid (SAHA) from its α,?-didehydro derivative is described. The didehydro derivative is obtained through a cross metathesis reaction between a suitable terminal alkene and N-benzyloxyacrylamide. Some of the didehydro derivatives of SAHA were preliminarily evaluated for anticancer activity towards HeLa cells. The administration of the analogues caused a significant decrease in the proliferation of HeLa cells. Furthermore, one of the analogues showed a maximum cytotoxicity with a minimum GI50 value of 2.5 μg/mL and the generation of reactive oxygen species (ROS) as some apoptotic features.
- Chattopadhyay, Shital K.,Ghosh, Subhankar,Sarkar, Sarita,Bhadra, Kakali
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- A nanodelivered Vorinostat derivative is a promising oral compound for the treatment of visceral leishmaniasis
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There is currently no satisfactory treatment for visceral leishmaniasis; the disease is thus in desperate need of novel drugs. The ideal candidate should be effective, safe, affordable, and administered via the oral route. Histone deacetylases (HDACs) are involved in silencing critical regulatory pathways, including pro-apoptotic programs, and represent potential therapeutic targets for pharmacological interventions. O-alkyl hydroxamates have traditionally been considered to exert no effect on mammal HDACs. The aim of this study was to evaluate the effect of MDG, a SAHA derivative of the O-alkyl hydroxamate family with no activity on human histone deacetylase enzymes, on the visceral leishmaniasis causative agents and in a murine model of the disease. The effects of vorinostat, tubacin and valproic acid (well-known mammal HDAC inhibitors) on the parasite were also evaluated. MDG was found to be highly active against Leishmania infantum and L. donovani intracellular amastigotes in vitro but not against the promastigote stage. In contrast, vorinostat, tubacin and valproic acid showed no activity against the parasite. Assays investigating hERG and Cav1.2 channels in vitro found no evidence of MDG-driven cardiotoxicity. MDG showed neither hepatotoxicity nor mutagenicity, nor did it exert activity on cytochrome P450 enzymes. MDG was adsorbed onto gold nanoparticles for the in vivo experiments, performed on infected Balb/c mice. MDG was effective at reducing the parasite load in major target tissues (bone marrow, spleen and liver) in more than 70% at 25 mg/kg through both the oral and intraperitoneal route, proving more active than the reference compounds (meglumine antimoniate, MA) without showing toxicity. In addition, the combination of MDG and MA was very effective.
- Corpas-López, Victoriano,Díaz-Gavilán, Mónica,Franco-Montalbán, Francisco,Merino-Espinosa, Gemma,López-Viota, Margarita,López-Viota, Julián,Belmonte-Reche, Efres,Pérez-del Palacio, José,de Pedro, Nuria,Gómez-Vidal, José Antonio,Morillas-Márquez, Francisco,Martín-Sánchez, Joaquina
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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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- 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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- A new simple and high-yield synthesis of suberoylanilide hydroxamic acid and its inhibitory effect alone or in combination with retinoids on proliferation of human prostate cancer cells
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We have developed a procedure for the synthesis of TV-hydroxy-N 1-phenyloctanediamide (suberoylanilide hydroxamic acid (SAHA)), providing the product in 79.8% yield. SAHA is a potent inhibitor of histone deacetylase, induces differentiation and/or apoptosis in certain transformed cells in culture, and suppressed the growth of human prostate cancer LNCaP and PC-3 cell lines. The combination of SAHA with other compounds inhibited cell proliferation of LNCaP cells in additive fashion and resulted in synergistic growth inhibition.
- Gediya, Lalji K.,Chopra, Pankaj,Purushottamachar, Puranik,Maheshwari, Neha,Njar, Vincent C. O.
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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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- 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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- A method for utilizing the modified mesoporous material catalytic preparation fu linuo his method (by machine translation)
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The invention provides a coupling agent suberic acid bitter wine and modified mesoporous silica coupling/catalytic system for preparing fu linuo his method, the method comprises the following steps: preparation suberic acid bitter wine and coupling agent modified mesoporous silicon dioxide; wherein said hydrophilic modified mesoporous silicon dioxide pre-treatment reactant [...] 1 - 2 h, with aniline or a salt thereof to react to form an intermediate product of bromoxynil aniline acid; in the presence of a modified mesoporous silica obtained bromoxynil aniline acid with hydroxylamine or its salt by the reaction of the fu linuo he. The method of the invention the selectivity and the yield is high, the amidation reaction time is short, the resulting fu linuo he purity as high as 99% or more. (by machine translation)
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Paragraph 0034; 0037
(2019/01/23)
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- Method for rapidly preparing vorinostat from 7-anilinoformyl methyl heptanoate
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The invention discloses a method for preparing an anti-cancer drug of vorinostat from 7-anilinoformyl methyl heptanoate. The method comprise the following steps of, firstly, adding excessive alkali into methanol solution containing a certain amount of hydroxylamine hydrochloride, after the mixture is uniformly mixed, maintaining an alkaline environment at a certain pH; secondly increasing the mixture to a certain temperature, adding a certain amount of 7-anilinoformyl methyl heptanoate for reaction, after reaction is completed, performing rotary evaporation to remove solvent, adding a certainvolume of 5 mol/L diluted hydrochloric acid into obtained products for intensive mixing; lastly, performing suction filtration and multiple washing, and then drying obtain white solid in vacuum to obtain high-purity vorinostat. The method for rapidly preparing the vorinostat from the 7-anilinoformyl methyl heptanoate innovatively detects that preprocessing the hydroxylamine hydrochloride throughsodium hydroxide and maintaining the alkaline environment are very beneficial to positive reaction shift and can substitute for traditional preprocessing processes with sodium methoxide, thereby greatly shortening the reaction time, improving the productivity rate, reducing the cost and achieving a broad industrialization prospect.
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Paragraph 0011; 0032; 0058-0064; 0067; 0074; 0081; 0087
(2018/06/04)
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- Pendant HDAC inhibitor SAHA derivatised polymer as a novel prodrug micellar carrier for anticancer drugs
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Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACi) approved by FDA for the treatment of cutaneous T cell lymphoma, is a promising anticancer drug for various cancers with a unique mode of action. However, it demonstrates limited clinical benefits in solid tumours as a single drug. In order to achieve enhanced and synergistic co-delivery of SAHA and doxorubicin (DOX), a cleavable SAHA-based prodrug polymer (POEG-b-PSAHA), consisting of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) blocks and hydrophobic SAHA segments, has been developed. POEG-b-PSAHA prodrug polymer was able to form spherical micelles with a diameter around 60 nm and well retained the pharmacological activity of SAHA in either inhibiting the proliferation of tumour cells or inducing histone acetylation. DOX formulated in POEG-b-PSAHA-based micelles showed a sustained release profile. DOX-loaded POEG-b-PSAHA exhibited more potent cytotoxicity towards tumour cells than free DOX and DOX loaded in a pharmacologically ‘inert’ nanocarrier, POEG-b-POM. Consistently, DOX/POEG-b-PSAHA formulation resulted in an improved therapeutic effect in vivo compared to free DOX, Doxil or DOX formulated in POEG-b-POM micelles. These results suggest that SAHA-based prodrug micelles may serve as a dual functional carrier for combination strategies in epigenetic-oriented anticancer therapy.
- Xu, Jieni,Sun, Jingjing,Wang, Pengcheng,Ma, Xiaochao,Li, Song
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p. 448 - 457
(2018/01/01)
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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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- Unique physicochemical and catalytic properties dictated by the B3NO2 ring system
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The expansion of molecular diversity beyond what nature can produce is a fundamental objective in chemical sciences. Despite the rich chemistry of boron-containing heterocycles, the 1,3-dioxa-5-aza-2,4,6-triborinane (DATB) ring system, which is characterized by a six-membered B3NO2 core, remains elusive. Here, we report the synthesis of m-terphenyl-templated DATB derivatives, displaying high stability and peculiar Lewis acidity arising from the three suitably arranged boron atoms. We identify a particular utility for DATB in the dehydrative amidation of carboxylic acids and amines, a reaction of high academic and industrial importance. The three boron sites are proposed to engage in substrate assembly, lowering the entropic cost of the transition state, in contrast with the operative mechanism of previously reported catalysts and amide coupling reagents. The distinct mechanistic pathway dictated by the DATB core will advance not only such amidations, but also other reactions driven by multisite activation.
- Noda, Hidetoshi,Furutachi, Makoto,Asada, Yasuko,Shibasaki, Masakatsu,Kumagai, Naoya
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p. 571 - 577
(2017/06/01)
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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 0047; 0048
(2017/06/02)
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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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p. 6964 - 6967
(2016/05/11)
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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; 0027
(2017/06/23)
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- Synergistic effect of the combination of novel suberoylanilide hydroxamanic acid derivatives with cisplatin on anti-proliferation of human cancer cells
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A novel, green, and atom-economical boric acid catalyzed direct amidation without the use of any coupling agents for the preparation of suberoylanilide hydroxamic acid (SAHA) and SAHA-based inhibitors targeting anti-proliferation of cancer cells is provided. The new SAHA-based inhibitor B123, when used alone, exhibited higher anti-proliferative activities than SAHA or Cisplatin against a number of human cancer cells. We have examined the effect of combination of these SAHA-based inhibitors with Cisplatin. We found synergistic effects of the combination of SAHA-based inhibitors with Cisplatin over a wide range of concentrations against human liver cancer cells HepG2 and two human lung cancer cell lines H1299 and H460. This synergism leads up to 8-fold of dose reduction for Cisplatin in the combination with our synthesized inhibitor B123 against H1299.
- Xie, Rui,Shi, Jinghua,Cheng, Chunhui,Yun, Fan,Liu, Xia,Tang, Pingwah,Wu, Xinying,Yang, Ming,Yuan, Qipeng
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p. 767 - 774
(2016/11/29)
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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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p. 6108 - 6111
(2015/10/28)
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- Synthesis and anti-tumor activities of novel phenyl substituted suberoylanilide hydroxamic acid derivatives against human cancer cells
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A facile and atom-economical boric acid catalyzed direct amidation without any coupling agents for the preparation of Suberoylanilide Hydroxamic Acid (SAHA) and SAHA-based inhibitors targeting anti-proliferation of cancer cells is described. It is applicable to the preparation of SAHAbased inhibitors having an unprotected hydroxyl group in the phenyl ring without the need of the protection. The in-vitro assays data indicate that the nature and the position of the substituents (activating and/or deactivating) in the capping group (phenyl ring) of SAHA-based inhibitors synthesized in this study have a vital impact on the potency of anti-proliferative activity against cancer cells. With low toxicity toward the normal cells, a number of synthesized SAHA-based inhibitors with two substituents in the phenyl ring possess higher antiproliferative activity than SAHA and Cisplatin toward six studied cancer cell lines: A375 human skin cancer cells, A549 human lung cancer cells, MGC80-3 human gastric cancer cells, H460 human lung cancer cells, H1299 human lung cancer cells, and HepG2 human liver cancer cells. Cisplatin is a common chemotherapeutic drug with high cytotoxicity for a variety of cancer treatments. The inhibitors provided in this study might signify future therapeutic drugs for cancer treatment.
- Xie, Rui,Shi, Jinghua,Qu, Yue,Tang, Pingwah,Wu, Xinying,Yang, Ming,Yuan, Qipeng
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p. 636 - 648
(2015/11/28)
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- Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, induces the production of anti-inflammatory cyclodepsipeptides from Beauveria felina
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The addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid to a culture of the filamentous fungus Beauveria felina significantly changed its secondary metabolite profile and led to the isolation of eight compounds, including three new cyclodepsipeptides, desmethylisaridin E (1), desmethylisaridin C2 (2), and isaridin F (3), along with five known cyclodepsipeptide compounds. Isaridin F (3) possesses a cyclodepsipeptide ring with N-methylbutyric acid, which is rare in natural peptides. Absolute configurations of the new cyclodepsipeptides were achieved by Marfey's method. The anti-inflammatory activity of the isolated compounds was investigated through evaluating their effect on superoxide anion production and elastase release by FMLP-induced human neutrophils. Among the tested compounds, desmethylisaridin E (1) inhibited superoxide anion production and desmethylisaridin C2 (2) inhibited elastase release, with IC50 values of 10.00 ± 0.80 and 10.01 ± 0.46 μM, respectively.
- Chung, Yu-Ming,El-Shazly, Mohamed,Chuang, Da-Wei,Hwang, Tsong-Long,Asai, Teigo,Oshima, Yoshiteru,Ashour, Mohamed L.,Wu, Yang-Chang,Chang, Fang-Rong
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supporting information
p. 1260 - 1266
(2013/08/23)
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- Investigating the selectivity of metalloenzyme inhibitors
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The inhibitory activity of a broad group of known metalloenzyme inhibitors against a panel of metalloenzymes was evaluated. Clinically approved inhibitors were selected as well as several other reported metalloprotein inhibitors in order to represent a broad range of metal binding groups (MBGs), including hydroxamic acid, carboxylate, hydroxypyridinonate, thiol, and N-hydroxyurea functional groups. A panel of metalloenzymes, including carbonic anhydrase (hCAII), several matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), histone deacetylase (HDAC-2), and tyrosinase (TY), was selected based on their clinical importance for a range of pathologies. In addition, each inhibitor was evaluated for its ability to remove Fe3+ from holo-transferrin to gauge the ability of the inhibitors to access Fe 3+ from a primary transport protein. The results show that the metalloenzyme inhibitors are quite selective for their intended targets, suggesting that despite their ability to bind metal ions, metalloprotein inhibitors are not prone to widespread off-target enzyme inhibition activity.
- Day, Joshua A.,Cohen, Seth M.
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supporting information
p. 7997 - 8007
(2013/11/06)
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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 7
(2011/11/06)
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- Discovery of (2 E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5- yl}-N-hydroxyacrylamide (SB939), an orally active histone deacetylase inhibitor with a superior preclinical profile
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A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC 50), liver microsomal stability (t1/2), cytochrome P450 inhibitory (3A4 IC50), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.
- Wang, Haishan,Yu, Niefang,Chen, Dizhong,Lee, Ken Chi Lik,Lye, Pek Ling,Chang, Joyce Wei Wei,Deng, Weiping,Ng, Melvin Chi Yeh,Lu, Ting,Khoo, Mui Ling,Poulsen, Anders,Sangthongpitag, Kanda,Wu, Xiaofeng,Hu, Changyong,Goh, Kee Chuan,Wang, Xukun,Fang, Lijuan,Goh, Kay Lin,Khng, Hwee Hoon,Goh, Siok Kun,Yeo, Pauline,Liu, Xin,Bonday, Zahid,Wood, Jeanette M.,Dymock, Brian W.,Kantharaj, Ethirajulu,Sun, Eric T.
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supporting information; experimental part
p. 4694 - 4720
(2011/09/15)
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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 19
(2010/04/30)
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- Modified cap group suberoylanilide hydroxamic acid histone deacetylase inhibitor derivatives reveal improved selective antileukemic activity
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A series of SAHA cap derivatives was designed and prepared in good-to-excellent yields that varied from 49% to 95%. These derivatives were evaluated for their antiproliferative activity in several human cancer cell lines. Antiproliferative activity was observed for concentrations varying from 0.12 to >100 μM, and a molecular modeling approach of selected SAHA derivatives, based on available structural information of human HDAC8 in complex with SAHA, was performed. Strikingly, two compounds displayed up to 10-fold improved antileukemic activity with respect to SAHA; however, these compounds displayed antiproliferative activity similar to SAHA when assayed against solid tumor-derived cell lines. A 10-fold improvement in the leukemic vs peripheral blood mononuclear cell therapeutic ratio, with no evident in vivo toxicity toward blood cells, was also observed. The herein-described compounds and method of synthesis will provide invaluable tools to investigate the molecular mechanism responsible for the reported selectively improved antileukemic activity.
- Salmi-Smail, Chanaz,Fabre, Aurélie,Dequiedt, Franck,Restouin, Audrey,Castellano, Rémy,Garbit, Slaveia,Roche, Philippe,Morelli, Xavier,Brunel, Jean Michel,Collette, Yves
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experimental part
p. 3038 - 3047
(2010/09/07)
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- POLYMORPHS OF VORINOSTAT AND VORINOSTAT POTASSIUM SALT AND PROCESS FOR PREPARATION THEREOF
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Crystalline Vorinostat potassium salt form A characterized by a powder XRD pattern having peaks at about 4.9 and 7.4 ± 0.2 degrees 2-theta and any 3 peaks selected from the lis consisting of: 12.3, 19.8, 20.9, 22.1, 22.8, 28.7 and 29.5 ± 0.2 degrees 2-theta is provided. Crystalline Vorinostat potassium salt form A may be polymorphically pure. Processes for preparing crystalline Vorinostat potassium salt form A are also provided. Further provided i crystalline Vorinostat form VI characterized by a powder XRD pattern having peaks at about 14.3, 14.8, 17.6, 21.4 and 23.1 ± 0.2 degrees 2-theta as well as processes for preparing crystalline Vorinostat form VI.
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Page/Page column 10
(2010/06/17)
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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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- OCULAR HYPOTENSIVE AGENT COMPRISING COMPOUND CAPABLE OF INHIBITING HISTONE DEACETYLASE AS ACTIVE INGREDIENT
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An object of the present invention is to find a novel pharmacological effect of a compound having an HDAC inhibitory effect. The compound having an HDAC inhibitory effect of the invention has an excellent effect of cell morphological change on trabecular meshwork cells and/or effect of intraocular pressure reduction, and is therefore useful as a preventive and/or therapeutic agent for a disease considered to be associated with aqueous humor circulation and/or intraocular pressure, particularly as a preventive and/or therapeutic agent for glaucoma or ocular hypertension.
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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
(2008/12/05)
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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 33-34
(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 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 60-61
(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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- 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 11-12; 36
(2008/06/13)
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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 84-85
(2008/06/13)
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- Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
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The present invention provides the compound having the formula: wherein each of R1and R2is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, t-butyl, aryloxy, arylalkyloxy, or pyridine group; wherein A is an amido moiety, —O—, —S—, —NH—, or —CH2—; and wherein n is an integer from 3 to 8. The present invention also provides a method of selectively inducing growth arrest, terminal differentiation and/or apoptosis of neoplastic cells and thereby inhibiting proliferation of such cells. Moreover, the present invention provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells. Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of the compound above.
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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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