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PubMed1998

Selective inhibition of low affinity IgE receptor (CD23) processing.

A series of hydroxamic acids related to the non-selective matrix metalloproteinase inhibitor Batimastat has been prepared, some members of which are potent inhibitors of the processing of the low affinity IgE receptor (CD 23). Increased activity is obtained by appropriate substitution at the alpha-position, whilst selectivity is gained by use of a P1' benzyl group in conjunction with a C-terminal primary amide.

Hydroxamic Acids↗
PubMed1976

The use of chang cells cultured in vitro to evaluate potential iron chelating drugs.

A number of iron chelating agents, consisting largely of hydroxamic acid and benzoic acid derivatives, have been studied in an in vitro Chang cell culture system to determine their effect on cellular iron uptake, ferritin synthesis and the incorporation of iron into ferritin. The results have been compared with those of a previous study in which iron balance was determined in hypertransfused rats. Both techniques appear to be of value in screening new iron chelating agents for potential therapeutic use in patients with iron overload.

Benzoates↗
PubMed2003

An activated receptor tyrosine kinase, TEL/PDGFbetaR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice.

The t(8;21)(q22;q22) translocation, occurring in 40% of patients with acute myeloid leukemia (AML) of the FAB-M2 subtype (AML with maturation), results in expression of the RUNX1-CBF2T1 [AML1-ETO (AE)] fusion oncogene. AML/ETO may contribute to leukemogenesis by interacting with nuclear corepressor complexes that include histone deacetylases, which mediate the repression of target genes. However, expression of AE is not sufficient to transform primary hematopoietic cells or cause disease in animals, suggesting that additional mutations are required. Activating mutations in receptor tyrosine kinases (RTK) are present in at least 30% of patients with AML. To test the hypothesis that activating RTK mutations cooperate with AE to cause leukemia, we transplanted retrovirally transduced murine bone marrow coexpressing TEL-PDGFRB and AE into lethally irradiated syngeneic mice. These mice (19/19, 100%) developed AML resembling M2-AML that was transplantable in secondary recipients. In contrast, control mice coexpressing with TEL-PDGFRB and a DNA-binding-mutant of AE developed a nontransplantable myeloproliferative disease identical to that induced by TEL-PDGFRB alone. We used this unique model of AML to test the efficacy of pharmacological inhibition of histone deacetylase activity by using trichostatin A and suberoylanilide hydroxamic acid alone or in combination with the tyrosine kinase inhibitor, imatinib mesylate. We found that although imatinib prolonged the survival of treated mice, histone deacetylase inhibitors provided no additional survival benefit. These data demonstrate that an activated RTK can cooperate with AE to cause AML in mice, and that this system can be used to evaluate novel therapeutic strategies.

3T3 Cells↗
PubMed1997

NMR studies of the role of hydrogen bonding in the mechanism of triosephosphate isomerase.

Triosephosphate isomerase (TIM) catalyzes the reversible interconversion of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP), with Glu-165 removing the pro-R proton from C1 of DHAP and neutral His-95 polarizing the carbonyl group of the substrate. TIM and its complexes with the reactive intermediate analogs, phosphoglycolic acid (PGA) and phosphoglycolohydroxamic acid (PGH), were studied by 1H NMR at 600 MHz and at low temperature (-4.8 degrees C). His-95 shows an N epsilon H resonance at 13.1 ppm which shifts to 13.3 ppm in the TIM-PGA complex and to 13.5 ppm in the TIM-PGH complex. In the TIM-PGH complex, His-95 N epsilon H shows a slow, pH-independent exchange rate with water (kex = 80 s-1 at 30 degrees C, Eact = 19 kcal/mol), which is 44-fold slower than that of an exposed histidine suggesting partial shielding from bulk solvent, and a fractionation factor phi = 0.71 +/- 0.02 consistent with its donation of a normal hydrogen bond. The formation of the TIM-PGH complex results in the appearance of several deshielded proton resonances, including one at 14.9 ppm and one at 10.9 ppm which overlaps with another resonance. The resonance at 14.9 ppm is absent and the resonance at 10.9 ppm is much weaker in the TIM complex of PGA, which lacks the hydroxamic acid (-NHOH) moiety. 15N-labeled PGH was synthesized and the NH proton of free [15N]PGH shows a single 1H-15N HMQC cross peak with delta (1H) = 10.3 ppm and delta (15N) = 168 ppm which shifts to delta (1H) = 10.9 ppm and delta (15N) = 174 ppm in the TIM complex of [15N]PGH. The 15N-1H coupling in the complex indicates covalent N-H bonding, and the deshielded delta (15N) indicates a significant contribution of the imidate resonance form of PGH. The 14.9 ppm resonance is assigned to the NOH proton of bound PGH. This resonance shows a pH-independent exchange rate with water (kex = 3900 s-1 at 30 degrees C, Eact = 8.9 kcal/mol) which may reflect the dissociation of the TIM-PGH complex, and meets the criteria for a low-barrier hydrogen bond on the basis of the significant downfield shift of 6.2 ppm from the NOH proton of the model compound acetohydroxamic acid, and a very low fractionation factor phi = 0.38 +/- 0.06. In the X-ray structure of the TIM-PGH complex [Davenport, R. C., Bash, P. A., Seaton, B. A., Karplus, M., Petsko, G. A., and Ringe, D. (1991) Biochemistry 30, 5821], the NOH proton of bound PGH is hydrogen bonded to Glu-165. A low-barrier hydrogen bond from PGH NOH to Glu-165 suggests a dual role for Glu-165 in catalysis of proton transfer not only between the C1 and C2 carbons but also between the O1 and O2 oxygens in the interconversion of DHAP and GAP in wild type TIM. Such a mechanism, together with the measured exchange rate of the His-95 N epsilon H proton with solvent protons can accommodate the classical measurements of tritium incorporation from DHAP into GAP.

Computer Simulation↗
PubMed1977

EPR studies of higher plant mitochondria. I Ubisemiquinone and its relation to alternative respiratory oxidations.

An EPR investigation of the region of the higher plant respiratory chain involving ubiquinone and Center S-3 of succinate dehydrogenase is reported. At temperatures close to those of liquid helium, first derivative spectra corresponding to Center S-3 (gmax = 2.017) and a signal split around g = 2.00 (major features of peaks and troughs at g values of 2.045, 2.03, 1.985, 1.97 and 1.96) were observed in mung bean (Phaseolus aureus), Arum maculatum spadix, Sauromatum guttatum spadix and tulip bulb (Tulipa gesnerana) mitochondria. The split signal was small or absent in potato tuber and Symplocarpus foetidus spadix mitochondria. The redox behavior of these signals in mung bean mitochondria in a variety of respiratory steady-state conditions suggested that the components giving rise to them were an integral part of the respiratory chain and were located on the substrate side of coupling Site II. The split signal could be removed by addition of hydroxamic acids in all tissues tested, although the Ks of this effect was an order of magnitude higher than the Ki of inhibition of the alternative respiratory pathway in mung bean and Sauromatum guttatum spadix mitochondria. The results are discussed in relation to the current ideas on the ordering of components in the region around the classical Site II of the respiratory chain and in relation to the location of the alternative respiratory oxidase pathway of higher plants.

Cyanides↗
PubMed2006

Histone deacetylase inhibitors induce cell death in supratentorial primitive neuroectodermal tumor cells.

Histone deacetylase inhibitors (HDIs) are a promising new class of antineoplastic agents with the capacity to induce differentiation and/or apoptosis of cancer cells. The objective of this study was to evaluate the activity of HDIs against supratentorial primitive neuroectodermal tumor (sPNET) cells. We show that the HDIs, suberoylanilide hydroxamic acid, sodium butyrate, and trichostatin A, induced cell death, and activated caspase-3 and -9 in a sPNET cell line, PFSK. The poly-caspase inhibitor z-VAD-fmk partially prevented the action of HDIs, as judged by determining the mitochondrial membrane potential and by quantifying internucleosomal DNA fragmentation. In conclusion, the HDIs explored possess potent activity against sPNET cells, suggesting that HDIs may be effective in the treatment of sPNET.

Acetylation↗
PubMed1997

The proteoglycan metabolism, morphology and viability of articular cartilage treated with a synthetic matrix metalloproteinase inhibitor.

Matrix metalloproteinases (MMP) are among the key enzymes responsible for the proteolytic destruction of articular cartilage during chronic rheumatic diseases. Articular cartilage is one potential target for drugs designed to inhibit the activity of MMPs in order to stop or to slow down the proteolytic destruction of the extracellular matrix of cartilage. The purpose of this study was to investigate the effect of the synthetic inhibitor of MMPs U-24522 for its ability (1) to inhibit in vitro the activity of MMP-proteoglycanases; (2) to modulate the morphology and viability of cartilage explants; and (3) to modify the biosynthesis and release of proteoglycans from articular cartilage explants. U-24522 dose-dependently inhibited the activity of MMP-proteoglycanases and significantly reduced the release of proteoglycans from interleukin-1 treated bovine articular cartilage explants when tested at concentrations ranging from 10(-4) to 10(-9) M. This hydroxamic acid derivative proved not to be harmful to chondrocyte viability and cartilage morphology. In addition, U-24522 had no effect on the rate of proteoglycan biosynthesis of interleukin-1 treated cartilage explants and increased the percentage of newly synthesized proteoglycans to form macromolecular aggregates. Thus U-24522 combines direct inhibitory potential on the activity of MMP-proteoglycanases with the inhibition of interleukin-1 stimulated proteoglycan loss from articular cartilage explants without affecting the morphology, viability and biosynthesis of proteoglycans of bovine articular cartilage explants.

Animals↗
PubMed1998

Oxidized thiols markedly amplify the vascular response to balloon injury in rabbits through a redox active metal-dependent pathway.

OBJECTIVE: Our aim was to assess whether exposure to oxidized thiols--a known usual consequence of oxidant stress--has the potential to affect the vascular repair response to angioplasty-induced injury. In addition, we also assessed the role of redox active metals in disulfide effects. METHODS: In 82 rabbits submitted to overdistention of iliac arteries, the following variables were analyzed: neointimal thickening, immunoreactivity to Proliferating Cell Nuclear Antigen, and cellular and collagen densities. RESULTS: A single intraarterial challenge of oxidized glutathione (GSSG, 6.5 mumol/kg) during and immediately after injury triggered a marked increase of the vascular repair reaction, as follows: (A) at day 7 after injury, there was a 2.7-fold increase in proliferation (p < 0.001 vs. control); (B) at day 14, there was increase of intimal/medial area ratio to 1.35 +/- 0.14, vs. 0.56 +/- 0.08 in controls. Proliferating cells increased to 5.5 +/- 0.8 cells/mm2, vs. 2.2 +/- 0.5 in controls (p < 0.002 for both variables). Overall cellularity was enhanced 2.2-fold; (C) at day 28, there was ongoing vessel wall proliferation, contrarily to controls. All GSSG effects were completely prevented by co-infusion of reduced glutathione (GSH) and were mimicked by cystine (6.5 mumol/kg). The uninjured artery showed no response to disulfides. To assess the role of redox active metals in GSSG action, the effects of 1,10-phenanthroline or N-CBZ-Pro-Leu-Gly hydroxamic acid (HXA), metal chelators with metalloproteinase inhibitor properties, were evaluated. Both compounds totally blocked the GSSG-induced amplification of vascular responses. In rabbits not exposed to GSSG, HXA decreased neointimal thickening by 50% (p < 0.05). CONCLUSIONS: Exposure to excess disulfide levels early after vascular balloon injury markedly amplified the late cellular response through interaction with redox active metals. These pathways can potentially mediate noxious effects of oxidative stress in vessels.

Animals↗
PubMed1998

The design, synthesis, and structure-activity relationships of a series of macrocyclic MMP inhibitors.

A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.

Collagenases↗
PubMed2002

Inhibitors of human histone deacetylase: synthesis and enzyme and cellular activity of straight chain hydroxamates.

Inhibitors of histone deacetylase (HDAC) have been shown to induce terminal differentiation of human tumor cell lines and to have antitumor effects in vivo. We have prepared analogues of suberoylanilide hydroxamic acid (SAHA) and trichostatin A and have evaluated them in a human HDAC enzyme inhibition assay, a p21(waf1) (p21) promoter assay, and in monolayer growth inhibition assays. One compound, 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-benzamide, was found to affect the growth of a panel of eight human tumor cell lines differentially.

Antineoplastic Agents↗
PubMed1998

The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen rearrangement.

Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.

Administration, Oral↗
PubMed2005

Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species.

Interactions between histone deacetylase inhibitors (HDACIs) and the alkyl-lysophospholipid perifosine were examined in human leukemia cells. Coadministration of sodium butyrate, suberoylanilide hydroxamic acid (SAHA), or trichostatin with perifosine synergistically induced mitochondrial dysfunction (cytochrome c and apoptosis-inducing factor release), caspase-3 and -8 activation, apoptosis, and a marked decrease in cell growth in U937 as well as HL-60 and Jurkat leukemia cells. These events were associated with inactivation of extracellular signal-regulated kinase (ERK) 1/2 and Akt, p46 c-jun-NH2-kinase (JNK) activation, and a pronounced increase in generation of ceramide and reactive oxygen species (ROS). They were also associated with up-regulation of Bak and a marked conformational change in Bax accompanied by membrane translocation. Ectopic expression of Bcl-2 delayed but was ultimately ineffective in preventing perifosine/HDACI-mediated apoptosis. Enforced expression of constitutively active mitogen-activated protein kinase kinase (MEK) 1 or myristoylated Akt blocked HDACI/perifosine-mediated ceramide production and cell death, suggesting that MEK/ERK and Akt inactivation play a primary role in these phenomena. However, inhibition of JNK activation (e.g., by the JNK inhibitor SP600125) did not attenuate sodium butyrate/perifosine-induced apoptosis. In addition, the free radical scavenger N-acetyl-L-cysteine attenuated ROS generation and apoptosis mediated by combined treatment. Finally, the acidic sphingomyelinase inhibitor desipramine attenuated HDACI/perifosine-mediated ceramide and ROS production as well as cell death. Together, these findings indicate that coadministration of HDACIs with perifosine in human leukemia cells leads to Akt and MEK/ERK disruption, a marked increase in ceramide and ROS production, and a striking increase in mitochondrial injury and apoptosis. They also raise the possibility that combining these agents may represent a novel antileukemic strategy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Bioactive conformation of stromelysin inhibitors determined by transferred nuclear Overhauser effects.

The transferred nuclear Overhauser effect has been used to determine the biologically active conformations of two stromelysin inhibitors. Both inhibitors used in this study were hydroxamic acids generated via chemical synthesis. These structures, representing the conformation of each inhibitor bound to stromelysin, superimposed with excellent agreement. The study also provided information on the shape and orientation of the S2' and S1' pockets of the enzyme relative to thermolysin. Comparisons were made between stromelysin and thermolysin inhibitors to critically examine thermolysin as a template for stromelysin-inhibitor design. The enzyme-bound conformations of these stromelysin inhibitors were determined for use as a template in conformationally restricted drug design.

Computer Simulation↗
PubMed2003

Phosphorus-based SAHA analogues as histone deacetylase inhibitors.

[structure: see text] Three analogues of suberoyl anilide hydroxamic acid (SAHA) with phosphorus metal-chelating functionalities were synthesized as inhibitors of histone deacetylases (HDACs). The compounds showed weak activity for HeLa nuclear extracts (IC(50) = 0.57-6.1 mM), HDAC8 (IC(50) = 0.28-0.41 mM), and histone-deacetylase-like protein (HDLP, IC(50) = 0.33-1.9 mM), suggesting that the transition state of HDAC is not analogous to zinc proteases. Antiproliferative activity against A2780 cancer cells (IC(50) = 0.11-0.12 mM), comparable to SAHA (0.15 mM), was observed.

Antineoplastic Agents↗
PubMed1996

Antibacterial agents that inhibit lipid A biosynthesis.

Lipid A constitutes the outer monolayer of the outer membrane of Gram-negative bacteria and is essential for bacterial growth. Synthetic antibacterials were identified that inhibit the second enzyme (a unique deacetylase) of lipid A biosynthesis. The inhibitors are chiral hydroxamic acids bearing certain hydrophobic aromatic moieties. They may bind to a metal in the active site of the deacetylase. The most potent analog (with an inhibition constant of about 50 nM) displayed a minimal inhibitory concentration of about 1 microgram per milliliter against Escherichia coli, caused three logs of bacterial killing in 4 hours, and cured mice infected with a lethal intraperitoneal dose of E. coli.

Amidohydrolases↗
PubMed2006

Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha.

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) plays a critical role in transcriptional gene activation involved in tumor angiogenesis. A novel class of agents, the histone deacetylase (HDAC) inhibitors, has been shown to inhibit tumor angiogenesis and HIF-1 alpha protein expression. However, the molecular mechanism responsible for this inhibition remains to be elucidated. In the current study, we investigated the molecular link between HIF-1 alpha inhibition and HDAC inhibition. Treatment of the VHL-deficient human renal cell carcinoma cell line UMRC2 with the hydroxamic HDAC inhibitor LAQ824 resulted in a dose-dependent inhibition of HIF-1 alpha protein via a VHL-independent mechanism and reduction of HIF-1 alpha transcriptional activity. HIF-1 alpha inhibition by LAQ824 was associated with HIF-1 alpha acetylation and polyubiquitination. HIF-1 alpha immunoprecipitates contained HDAC activity. Then, we tested different classes of HDAC inhibitors with diverse inhibitory activity of class I versus class II HDACs and assessed their capability of targeting HIF-1 alpha. Hydroxamic acid derivatives with known activity against both class I and class II HDACs were effective in inhibiting HIF-1 alpha at low nanomolar concentrations. In contrast, valproic acid and trapoxin were able to inhibit HIF-1 alpha only at concentrations that are effective against class II HDACs. Coimmunoprecipitation studies showed that class II HDAC4 and HDAC6 were associated with HIF-1 alpha protein. Inhibition by small interfering RNA of HDAC4 and HDAC6 reduced HIF-1 alpha protein expression and transcriptional activity. Taken together, these results suggest that class II HDACs are associated with HIF-1 alpha stability and provide a rationale for targeting HIF-1 alpha with HDAC inhibitors against class II isozymes.

Carcinoma, Renal Cell↗
PubMedDate not supplied

[Inhibitory analysis of the respiration of bacteroids from the nodules of yellow lupine].

Oxygen uptake and reduction of C2H2 by bacteroids was found to be inhibited by low concentrations of cyanide and azide. However, oxygen uptake was not completely suppressed even by 10(-3) M KCN. Cyanide-resistant respiration was not inhibited by salicyl-hydroxamic acid, and seemed to be accomplished at the account of autoxidable flavo-proteins. A small light-reversible inhibition of respiration by carbon monoxide was found only in the bacteroids with a high rate of nitrogen fixation. Rotenone, antimycin A, and tenoyltrifluoroacetone inhibited oxygen uptake and methylene reduction. Nitrogen fixation, but not respiration, was inhibited by 2,4-dinitrophenol. An electron-transport chain coupled with phosphorylation is supposed to be built into the membranes of the bacteroids. The activity of peroxidase and cytochrome peroxidase was demonstrated in the bacteroids.

Antimycin A↗