Home About us Contact
|
Home About us Contact | ||
|
|
||
Hydroxamic Acids (hydroxamic + acid)
Kinds of Hydroxamic Acids Selected AbstractsMicrowave-Assisted Conversion of 4-Nitrophenyl Esters into O -Protected Hydroxamic AcidsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 18 2009Thomas Kurz Abstract The microwave-assisted synthesis of O -protected hydroxamic acids starting from 4-nitrophenyl esters and O -protected hydroxylamines is described. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source] Metal-Free, Aerobic Dioxygenation of Alkenes Using Hydroxamic Acids,ANGEWANDTE CHEMIE, Issue 26 2010Valerie Einmal Dioxygenierung bitte, aber ohne Metall: In Gegenwart von O2 oder Luft als einzigem Oxidans und einziger externer O-Atomquelle liefert eine Vielzahl ungesättigter Hydroxamsäuren cyclische Hydroxamate, die einfach in 1,2-Diole überführt werden können, wobei eine ausgezeichnete Stereokontrolle möglich ist. [source] ChemInform Abstract: Base-Mediated Rearrangement of Free Aromatic Hydroxamic Acids (ArCO,NHOH) to Anilines.CHEMINFORM, Issue 36 2009Yujiro Hoshino Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] ChemInform Abstract: Microwave-Assisted Transformation of Esters into Hydroxamic Acids.CHEMINFORM, Issue 8 2008Assunta Massaro Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Improved Solution- and Solid-Phase Preparation of Hydroxamic Acids from Esters.CHEMINFORM, Issue 43 2005Chih Y. Ho Abstract For Abstract see ChemInform Abstract in Full Text. [source] Pyran-Containing Sulfonamide Hydroxamic Acids: Potent MMP Inhibitors that Spare MMP-1.CHEMINFORM, Issue 41 2004Lawrence A. Reiter Abstract For Abstract see ChemInform Abstract in Full Text. [source] Base-Mediated Reaction of N-Alkyl-O-acyl Hydroxamic Acids: Synthesis of 3-Oxo-2,3-dihydro-4-isoxazole Carboxylic Ester Derivatives.CHEMINFORM, Issue 4 2004Andrew J. Clark Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: Cyclic Hydroxamic Acids as Oxygenating Agents , Conversion of Imines to Anilides.CHEMINFORM, Issue 3 2002D. Sahadeva Reddy Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] ChemInform Abstract: Arylsulfonyl Hydroxamic Acids: Potent and Selective Matrix Metalloproteinase Inhibitors.CHEMINFORM, Issue 37 2001Andrew D. Baxter Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancerINTERNATIONAL JOURNAL OF CANCER, Issue 12 2008Mari Björkman Abstract Gene fusions between prostate-specific, androgen responsive TMPRSS2 gene and oncogenic ETS factors, such as ERG, occur in up to 50% of all prostate cancers. We recently defined a gene signature that was characteristic to prostate cancers with ERG activation. This suggested epigenetic reprogramming, such as upregulation of histone deactylase 1 (HDAC1) gene and downregulation of its target genes. We then hypothesized that patients with ERG -positive prostate cancers may benefit from epigenetic therapy such as HDAC inhibition (HDACi), especially in combination with antiandrogens. Here, we exposed ERG -positive prostate cancer cell lines to HDAC inhibitors Trichostatin A (TSA), MS-275 and suberoylanilide hydroxamic acid (SAHA) with or without androgen deprivation. We explored the effects on cell phenotype, gene expression as well as ERG and androgen receptor (AR) signaling. When compared with 5 other prostate cell lines, ERG -positive VCaP and DuCap cells were extremely sensitive to HDACi, in particular TSA, showing synergy with concomitant androgen deprivation increasing apoptosis. Both of the HDAC inhibitors studied caused repression of the ERG -fusion gene, whereas the pan-HDAC inhibitor TSA prominently repressed the ERG -associated gene signature. Additionally, HDACi and flutamide caused retention of AR in the cytoplasm, indicating blockage of androgen signaling. Our results support the hypothesis that HDACi, especially in combination with androgen deprivation, is effective against TMPRSS2-ERG -fusion positive prostate cancer in vitro. Together with our previous in vivo observations of an "epigenetic reprogramming gene signature" in clinical ERG -positive prostate cancers, these studies provide mechanistic insights to ERG -associated tumorigenesis and suggest therapeutic paradigms to be tested in vivo. © 2008 Wiley-Liss, Inc. [source] Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acidJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2004Douglas C. Marchion Abstract Acetylation of histones leads to conformational changes of DNA. We have previously shown that the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), induced cell cycle arrest, differentiation, and apoptosis. In addition to their antitumor effects as single agents, HDAC inhibitors may cause conformational changes in the chromatin, rendering the DNA more vulnerable to DNA damaging agents. We examined the effects of SAHA on cell death induced by topo II inhibitors in breast cancer cell lines. Topo II inhibitors stabilize the topo II,DNA complex, resulting in DNA damage. Treatment of cells with SAHA promoted chromatin decondensation associated with increased nuclear concentration and DNA binding of the topo II inhibitor and subsequent potentiation of DNA damage. While SAHA-induced histone hyperacetylation occurred as early as 4 h, chromatin decondensation was most profound at 48 h. SAHA-induced potentiation of topo II inhibitors was sequence-specific. Pre-exposure of cells to SAHA for 48 h was synergistic, whereas shorter pre-exposure periods abrogated synergy and exposure of cells to SAHA after the topo II inhibitor resulted in antagonistic effects. Synergy was not observed in cells with depleted topo II levels. These effects were not limited to specific types of topo II inhibitors. We propose that SAHA significantly potentiates the DNA damage induced by topo II inhibitors; however, synergy is dependent on the sequence of drug administration and the expression of the target. These findings may impact the clinical development of combining HDAC inhibitors with DNA damaging agents. © 2004 Wiley-Liss, Inc. [source] ORIGINAL ARTICLE: Solubilization of vorinostat by cyclodextrinsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2010Y. Y. Cai BSc Summary Background:, Vorinostat (suberoylanilide hydroxamic acid) is the first histone deacetylase inhibitor approved by US FDA for use in oncology. However, as a hydrophobic acid, its limited aqueous solubility poses a problem for parenteral delivery. Such limited solubility may also affect its oral bioavailability. Objective:, The aim of this study was to evaluate whether cyclodextrins (CDs), common excipients used in pharmaceutical industry, could increase the aqueous solubility of vorinostat. Methods:, The actual aqueous solubility of vorinostat was investigated by phase-solubility method. Molecular simulation was employed to predict the interaction energy and preferred orientation of vorinostat in CD cavities. Results:, Phase-solubility studies indicated that the solubility of vorinostat (7·24 × 10,1 mm) was substantially increased when complexed with various CDs, in the following order: randomly methylated-,-cyclodextrin (RM-,-CD) > hydroxypropyl-,-cyclodextrin (HP-,-CD) > ,-cyclodextrin > hydroxypropyl-,-cyclodextrin > Hydroxypropyl-,-cyclodextrin > ,-cyclodextrin. RM-,-CD 300 mm increased vorinostat solubility to 70·8 mm, almost two orders of magnitude higher than the baseline solubility. Such findings were in good agreement with the results obtained from molecular simulation. Conclusion:, CDs, particularly RM-,-CD and HP-,-CD, increased vorinostat's solubility. Future studies could be focused on the application of HP-,-CD in parenteral delivery of vorinostat or using RM-,-CD as an oral absorption enhancer. Molecular simulation appeared to be a useful tool for the selection of appropriate CD as excipient for drug delivery. [source] Thioredoxin system inhibitors as mediators of apoptosis for cancer therapyMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 1 2009Kathryn F. Tonissen Abstract The thioredoxin (Trx) system is a major antioxidant system integral to maintaining the intracellular redox state. It contains Trx, a redox active protein, which regulates the activity of various enzymes including those that function to counteract oxidative stress within the cell. Trx can also scavenge reactive oxygen species (ROS) and directly inhibits proapoptotic proteins such as apoptosis signal-regulating kinase 1 (ASK1). The oxidized form of Trx is reduced by thioredoxin reductase (TrxR). The cytoplasm and mitochondria contain equivalent Trx systems and inhibition of either system can lead to activation of apoptotic signaling pathways. There are a number of inhibitors with chemotherapy applications that target either Trx or TrxR to induce apoptosis in cancer cells. Suberoylanilide hydroxamic acid (SAHA) is effective against many cancer cells and functions by up-regulating an endogenous inhibitor of Trx. Other compounds target the selenocysteine-containing active site of TrxR. These include gold compounds, platinum compounds, arsenic trioxide, motexafin gadolinium, nitrous compounds, and various flavonoids. Inhibition of TrxR leads to an accumulation of oxidized Trx resulting in cellular conditions that promote apoptosis. In addition, some compounds also convert TrxR to a ROS generating enzyme. The role of Trx system inhibitors in cancer therapy is discussed in this review. [source] A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat modelsARTHRITIS & RHEUMATISM, Issue 7 2009Vijaykumar M. Baragi Objective Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity. Methods Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA),induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors. Results A number of non,hydroxamic acid,containing compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1-0635 demonstrated nonexclusive binding. ALS 1-0635 inhibited bovine articular cartilage degradation in a dose-dependent manner (48.7% and 87.1% at 500 nM and 5,000 nM, respectively) and was effective in inhibiting interleukin-1,, and oncostatin M,induced C1,C2 release in human OA cartilage cultures. ALS 1-0635 modulated cartilage damage in the rat MIA model (mean ± SEM damage score 1.3 ± 0.3, versus 2.2 ± 0.4 in vehicle-treated animals). Most significantly, when treated twice daily with oral ALS 1-0635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity. Conclusion The compounds investigated in this study represent a novel class of MMP-13 inhibitors. They are mechanistically distinct from previously reported broad-spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP-13 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease-modifying osteoarthritis drugs. [source] Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphomaCANCER SCIENCE, Issue 1 2010Takashi Watanabe Vorinostat (suberoylanilide hydroxamic acid, SAHA, Zolinza) is a histone deacetylase inhibitor with clinical activity in cutaneous T-cell lymphoma (CTCL). A phase I trial of oral vorinostat was conducted in Japanese patients with malignant lymphoma. Vorinostat 100 or 200 mg was administered twice daily for 14 consecutive days followed by a 1-week rest interval. Of 10 patients enrolled, four had follicular lymphoma (FL), two mantle cell lymphoma (MCL), two diffuse large B-cell lymphoma, and two CTCL (median age, 60 years; median number of prior regimens, 3). Vorinostat was well tolerated up to 200 mg with only one of six patients developing a dose-limiting toxicity (DLT; Grade 3 anorexia/hypokalemia). Common Grade 3 events were reversible neutropenia (30%), thrombocytopenia, and hypermagnesemia (20% each). The median number of treatment cycles was five (range, 1,36); two patients were continuing treatment. The overall response rate was 40%, with two complete responses/unconfirmed (CRu) and one partial response among FL patients and one CRu among MCL patients. One FL patient maintained CRu for 18.0 months. The median time to achieve CRu among the three patients was 8 months. These data suggest that further investigations of vorinostat in non-Hodgkin lymphoma, focusing on FL and MCL, are warranted. (Cancer Sci 2009) [source] Synthesis of N -Hydroxycinnamides Capped with a Naturally Occurring Moiety as Inhibitors of Histone DeacetylaseCHEMMEDCHEM, Issue 4 2010Wei-Jan Huang Prof. Abstract Histone deacetylase (HDAC) inhibitors are regarded as promising therapeutics for the treatment of cancer. All reported HDAC inhibitors contain three pharmacophoric features: a zinc-chelating group, a hydrophobic linker, and a hydrophobic cap for surface recognition. In this study we investigated the effectiveness of osthole, a hydrophobic Chinese herbal compound, as the surface recognition cap in hydroxamate-based compounds as inhibitors of HDAC. Nine novel osthole-based N -hydroxycinnamides were synthesized and screened for enzyme inhibition activity. Compounds 9,d, 9,e, 9,g exhibited inhibitory activities (IC50=24.5, 20.0, 19.6,nM) against nuclear HDACs in HeLa cells comparable to that of suberoylanilide hydroxamic acid (SAHA; IC50=24.5,nM), a potent inhibitor clinically used for the treatment of cutaneous T-cell lymphoma (CTCL). While compounds 9,d and 9,e showed SAHA-like activity towards HDAC1 and HDAC6, compound 9,g was more selective for HDAC1. Compound 9,d exhibited the best cellular effect, which was comparable to that of SAHA, of enhancing acetylation of either ,-tubulin or histone H3. Molecular docking analysis showed that the osthole moiety of compound 9,d may interact with the same hydrophobic surface pocket exploited by SAHA and it may be modified to provide class-specific selectivity. These results suggest that osthole is an effective hydrophobic cap when incorporated into N -hydroxycinnamide-derived HDAC inhibitors. [source] Microwave-Assisted Conversion of 4-Nitrophenyl Esters into O -Protected Hydroxamic AcidsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 18 2009Thomas Kurz Abstract The microwave-assisted synthesis of O -protected hydroxamic acids starting from 4-nitrophenyl esters and O -protected hydroxylamines is described. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source] A HTS Assay for the Detection of Organophosphorus Nerve Agent ScavengersCHEMISTRY - A EUROPEAN JOURNAL, Issue 11 2010Ludivine Louise-Leriche Abstract A new pro-fluorescent probe aimed at a HTS assay of scavengers is able to selectively and efficiently cleave the PS bond of organophosphorus nerve agents and by this provides non-toxic phosphonic acid has been designed and synthesised. The previously described pro-fluorescent probes were based on a conventional activated POaryl bond cleavage, whereas our approach uses a self-immolative linker strategy that allows the detection of phosphonothioase activity with respect to a non-activated PSalkyl bond. Further, we have also developed and optimised a high-throughput screening assay for the selection of decontaminants (chemical or biochemical scavengers) that could efficiently hydrolyse highly toxic V -type nerve agents. A preliminary screening, realised on a small ,-nucleophile library, allowed us to identify some preliminary "hits", among which pyridinealdoximes, ,-oxo oximes, hydroxamic acids and, less active but more original, amidoximes were the most promising. Their selective phosphonothioase activity has been further confirmed by using PhX as the substrate, and thus they offer new perspectives for the synthesis of more potent V nerve agent scavengers. [source] | ||||||||||||||||||||||||||||