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PubMed1976

The development of new iron-chelating drugs.

2,3-Dihydroxybenzoic acid has been identified as a potentially useful iron-chelating drug. Accordingly, we have evaluated a series of derivatives of hydroxylated benzoic acids for their ability to induce iron excretion in the iron-overloaded rat. In addition, we have examined a number of hydroxamic acids and some other naturally occurring iron-chelating agents. Of the 26 benzoic acid derivatives studied, none appeared to be more effective than 2,3-dihydroxybenzoic acid, for reasons which are discussed. Rhodotorulic acid, a hydroxamic acid produced by and isolated from cultures of Rhodotorula pilimanae, was the most effective of all the compounds studied in inducing iron excretion. When administered parenterally, rholotorulic acid induced iron excretion via both the urinary and the fecal routes and was more than twice as potent (on a weight basis) as desferrioxamine. Two ferrous chelators, alpha, alpha-dipyridyl ad 1,10-phenanthroline, induced a moderate amount of iron excretion, suggesting that a pool of ferrous iron may be available for chelation.

Animals↗
PubMed2007

A new degradable hydroxamate linkage for pH-controlled drug delivery.

A new drug delivery system based on a hydrodegradable hydroxamate linkage was evaluated. The carrier support system was poly(N-hydroxyacrylamide), which was synthesized via free radical polymerization of acryloyl chloride in 1,4-dioxane, initiated with 2,2'-azobisisobutyronitrile. The poly(acryloyl chloride) was modified in two steps. First, N-hydroxysuccinimide was added to give the imide ester of poly(acryloyl). In the second step, the imide ester of poly(acryloyl) was reacted with either hydroxylamine or N-methylhydroxylamine to give the corresponding hydroxamic acid. The hydroxamide functionality was then used to link the model drug ketoprofen. All products and intermediates were characterized by elemental analysis and FTIR and 1H NMR spectra. In vitro drug release was performed under specific conditions to elucidate the influence of the pH, polymer microstructure, and temperature on the hydrolysis rate of the amido-ester bond that linked the drug to the macromolecule. The drug release rate from N-methylhydroxamic acid polymers was faster than from hydroxamic acid polymers. All polymers showed higher rates of drug release at higher pH values (9.0 > 7.4 > 2.0) and at higher temperatures (37 degrees C > 20 degrees C).

Chemistry, Pharmaceutical↗
PubMed2003

Effect of hydroxamic acid-based matrix metalloproteinase inhibitors on human gingival cells and Porphyromonas gingivalis.

BACKGROUND: Matrix metalloproteinases (MMPs) are considered to play key roles in tissue destruction during periodontitis. In this study, we evaluated the cytotoxicity of hydroxamic acid-based MMP inhibitors (ONO-4817, ONO-MI1-514, and ONO-MI1-570), and their inhibitory effects on MMP-2 and -9 activities and growth of Porphyromonas gingivalis. METHODS: Human gingival fibroblasts (HGF) and human gingival epithelial cells (HGE) were incubated with test inhibitors prior to investigating cell viability, cell proliferation, and mRNA expression for MMP-2 and -9. Gelatin zymography and a colorimetric MMP assay were performed to study the inhibitory effects on MMP-2 and -9 activities derived from HGF and HGE, respectively. The effect of MMP inhibitors on keratinocyte migration and P. gingivalis growth was also tested. RESULTS: Cell viability was not affected by any of the inhibitors at a final concentration of 50 microM, nor was cell proliferation at 20 microM. All inhibitors clearly inhibited MMP-2 produced by HGF and MMP-9 produced by HGE in a dose-dependent manner. No change was found in mRNA expression of MMPs by gingival cells treated with the inhibitors. ONO-4817 and ONO-MI1-514 inhibited keratinocyte migration. ONO-4817 showed a slightly inhibitory effect on the growth of P. gingivalis. CONCLUSION: Data obtained in this study support the potential use of the three MMP inhibitors for the prevention and treatment of periodontal disease.

Cell Movement↗
PubMed2001

Inhibitors of histone deacetylase as new anticancer agents.

Inhibitors of histone deacetylase (HDAC) are an emerging class of anticancer agents. They induce hyperacetylation in chromatin usually resulting in activation of certain genes. They induce terminal cell differentiation and/or apoptosis in cancer cells. Histone deacetylase activity is recruited by co-repressor proteins to certain regions of the chromatin and aberrant histone acetylation caused by that recruitment is responsible for the pathogenesis of certain cancers on a molecular level. Inhibitors of HDAC have been identified in natural sources and also synthetic inhibitors are available. The best studied inhibitor is trichostatin A, a hydroxamic acid that exerts its activity by complexation of a zinc ion that is supposed to mediate the acetamide cleavage at the catalytic site. There are several synthetic hydroxamic acids that bear resemblance to trichostatin. Another class of potent inhibitors are naturally occurring and synthetic cyclotetrapeptides that all contain an unusual amino acid with an epoxyketone, ketone or hydroxamic acid function in the side chain. Phenylacetate, phenylbutyrate, butyrate and similar short chain fatty acids are also weak inhibitors. Further inhibitors from natural sources are the epoxide depudecin and depsipeptide FR 901228. The benzamide MS-275 belongs to a new class of synthetic HDAC inhibitors and displays oral activity in animal models. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer is possible. Thus, inhibitors of HDAC are one of the most promising class of new anticancer agents. New screening assays are useful tools that will facilitate identification of further inhibitors.

Anti-Bacterial Agents↗
PubMed2003

[Isomeric phenanthridines from 1,2-dihydro-5-methyl-2'-nitro-[1,1'-biphenyl]-2,6-dicarboxylic acid esters].

Hydrolysis of the dienamine function of the dihydrobiphenyls 3 leads to a mixture of the tautomers 4A-C (NMR). The structures of the starting material 3a and the products 4cA and 4bC are confirmed by X-ray crystal analysis. The biphenyls 5 are formed by dehydrogenation of 3 with iodine, whereas 4b produced the additional iodinated compound 6. 4b reacts with manganese dioxide to yield the phenol 7a. Irradiation of the dihydrobiphenyls 3 with UV-A light gives the nitrosobiphenyls 8. In contrast, the nitrobiphenyl 7b and the lactam 10a are formed as photo products from 4c. The reduction of the nitro group of 5 with Fe/AcOH leads to the isomeric phenanthridines 10 and 11 by cyclization, whereas after reaction with Zn/NH4Cl the cyclic hydroxamic acids 12 and 13 are isolated. Compound 7a reacts with Zn/acetate buffer to yield only the hydroxamic acid 12. Ring closure takes place on treating the nitrosobiphenyls 8 with conc. hydrochloric acid, to yield the chloro-substituted hydroxamic acids 14. The half wave potentials of the dihydrobiphenyls 3 and 4 are measured by anodic oxidation using a rotating platinum electrode by means of differential pulse voltammetry. The dienamines 3 are more sensitive towards oxidation than the reference drug nifedipine; in contrast, the carba-analogues 4 are much more stable. The cyclic hydroxamic acids 13 and 14a are tested for their ability to inhibit 5-, 12- and 15-lipoxygenase. Compound 13 represents a weak inhibitor of 5-lipoxygenase in human whole blood.

Chemical Phenomena↗
PubMed1976

Comparative adduct formation of 4-aminobiphenyl and 2-aminofluorene derivatives with macromolecules of isolated liver parenchymal cells.

Isolated parenchymal cells of rat liver have been used in a study of the metabolic activation of derivatives of the carcinogens 4-aminobiphenyl and 2-aminofluorene. The formation of adducts of these compounds with cellular RNA and protein has been taken as evidence of their transformation to metabolites that are capable of spontaneous reaction with tissue macromolecules. The hydroxamic acid N-hydroxy-N-4-acetylaminobiphenyl was bound to RNA to a greater extent than were the amino-, hydroxylamino-, nitroso-, nitro-, acetylamino-, or azoxybiphenyl derivatives. RNA adducts of the hydroxamic acid retained little of the acetyl group. The structural requirements for binding and the nature of the bound derivatives are consistent with the activation of N-hydroxy-N-4-acetylaminobiphenyl by N leads to O acyltransfer. Approximately equal quantities of 4-nitrosobiphenyl and the hydroxamic acid were bound to protein, but far less of the nitroso derivative was incorporated into RNA. Adduct formation of N-hydroxy-N-2-acetylaminofluorene with RNA occurred with retention of the acetyl group and was dependent on the concentration of sulfate in the media. Consequently, reaction of the fluorenyl derivative with RNA probably resulted from conjugation of the hydroxamic acid with sulfate.

Acetates↗
PubMed2000

Kinetics and mechanism of iron(III) dissociation from the dihydroxamate siderophores alcaligin and rhodotorulic acid.

The kinetics and mechanism of siderophore ligand dissociation from their fully chelated Fe(III) complexes is described for the highly preorganized cyclic tetradentate alcaligin and random linear tetradentate rhodotorulic acid in aqueous solution at 25 degrees C (Fe2L3 + 6H+ reversible 2 Fe3+ aq + 3 H2L). At siderophore:Fe(III) ratios where Fe(III) is hexacoordinated, kinetic data for the H(+)-driven ligand dissociation from the Fe2L3 species is consistent with a singly ligand bridged structure for both the alcaligin and rhodotorulic acid complexes. Proton-driven ligand dissociation is found to proceed via parallel reaction paths for rhodotorulic acid, in contrast with the single path previously observed for the linear trihydroxamate siderophore ferrioxamine B. Parallel paths are also available for ligand dissociation from Fe2(alcaligin)3, although the efficiency of one path is greatly diminished and dissociation of the bis coordinated complex Fe(alcaligin)(OH2)2+ is extremely slow (k = 10(-5) M-1 s-1) due to the high degree of preorganization in the alcaligin siderophore. Mechanistic interpretations were further confirmed by investigating the kinetics of ligand dissociation from the ternary complexes Fe(alcaligin)(L) in aqueous acid where L = N-methylacetohydroxamic acid and glycine hydroxamic acid. The existence of multiple ligand dissociation paths is discussed in the context of siderophore mediated microbial iron transport.

Hydroxamic Acids↗
PubMed2006

Discovery of a new chemical lead for a matrix metalloproteinase inhibitor.

A series of N-benzoyl gamma-aminobutyric hydroxamic acids were synthesized and evaluated as matrix metalloproteinase inhibitors. First, we focused on chemical modification of the N-benzoyl residue. Introduction of electron-rich para-substituents was effective to increase the inhibitory activity. Especially, some of the analogs with relatively more planar N-acyl residues, such as 10 and 11, demonstrated more potent activity. Second, chemical modification of the gamma-aminobutyric hydroxamic acid moiety was carried out to optimize the three-dimensional arrangement of the two pharmacophores (hydroxamic acid and N-acyl residues). Among the tested, the gamma-aminobutyric hydroxamic acid moiety was found to be the best spacer for connecting the above-mentioned two pharmacophores. Synthesis and structure-activity relationships are discussed.

Drug Design↗
PubMed1997

The synthesis of enantiomerically pure, highly functionalized heterocycles: the products of amino acid based acylnitroso hetero Diels-Alder reactions.

The diastereoselectivities of several chiral acylnitroso dienophiles (9a-h, 12 and 15) derived from optically pure, N-protected alpha-amino hydroxamic acids (2a-h, 4 and 7) were determined in an intermolecular hetero Diels-Alder reaction with cyclopentadiene. The diastereomeric excesses ranged from 0 to 72%. Hydroxamic acids with polar functionality were examined extensively to determine the effect of hydrogen bonding on the cycloaddition. The largest increase in diastereoselectivity was observed with increasing the steric bulk at the alpha-position of the hydroxamic acids and not with potential hydrogen bonding interactions. The cycloadditions afforded synthetically useful quantities of functionally rich, enantiomerically pure heterocycles (10a-h, 11a-h, 13, 14, 16 and 17), which have been elaborated into a variety of biologically interesting products.

Amino Acids↗
PubMedDate not supplied

Microsomal N-hydroxylation of the glycolamide 2-(glycolylamino)fluorene to give the glycolylhydroxamic acid. A new xenobiotic reaction.

The glycolamide 2-(glycolylamino)fluorene was found to be metabolized in part by induced rat liver microsomes to the hydroxamic acid N-hydroxy-2-(glycolylamino)fluorene. This is the first report of the ability of a microsomal system to carry out the N-hydroxylation of a glycolamide. A comparison of the relative rates of metabolism of the acetyl and glycolyl amides of 2-aminofluorene showed that the former gave about twice as much of the hydroxamic acid as did the latter. On the other hand, the overall metabolism of the glycolamide was slightly more rapid than that of the acetyl congener. Both the glycolyl- and acetyl-derived hydroxamic acids were further metabolized to unknown products by microsomal preparations in the presence of NADPH.

Amides↗
PubMed2004

Synthesis of novel hydroxamate and non-hydroxamate histone deacetylase inhibitors.

Histone deacetylases (HDACs) alter the acetylation status of chromatin and thereby effect gene expression. The inappropriate recruitment of HDACs may be one mechanism by which oncogenes can alter gene expression in favor of excessive cell proliferation, making inhibition of HDACs a potential target for the development of small-molecule anticancer agents. As a consequence there are several HDAC inhibitors currently undergoing clinical trials for the treatment of solid and non-solid tumors. This review examines recent synthetic methods used to prepare the diverse family of HDAC inhibitors, and includes syntheses of several of the current clinical candidates. The review is divided into the structural classes of known HDAC inhibitors, including non-peptidic hydroxamic acids, non-hydroxamate analogs and cyclic peptides.

Acetylation↗
PubMed2002

[Pyridazino(3,4-c)quinolines and pyridazino(4,5-c)quinolines--synthesis and investigation of lipoxygenase inhibition].

The cyclic hemiketone acetal 6 reacts with hydrazine in tert-butanol to yield the 1-amino-2,3-dihydro-2-hydroxy-pyrrole 7, while in acetic acid a mixture of the 1-amino-pyrrole 8 and the 1,4-dihydropyridazine 9 is obtained. The X-ray crystal structure of 9 shows a boat conformation flattened about N-1 with respect to nifedipine. Removing the boc-group of 9 gives the tautomeric 2,5-dihydropyridazine 13. The lactams 15 and 17 and the cyclic hydroxamic acids 16 and 18, respectively, are synthesized from 13 or from its oxidation product 14 using reductive conditions. The cyclic hemiacetal 21 reacts with hydrazine in a different manner from 6. In acetic acid the 1-aminopyrrole 22 is formed, while ethanol yields the 1,4-dihydropyridazine 23. The pyridazine 24, obtained by dehydrogenation of 23, gives the lactam 25 and the hydroxamic acid 26, respectively, when the nitro-group is reduced. The dihydropyridazines 9, 11 and 23 are transformed photochemically to give the nitrosophenyl-pyridazines 19, 20 and 27. The chloro-substituted hydroxamic acid 28 is isolated after treatment of 27 with hydrochloric acid. The stability of the partially saturated pyridazine compounds is discussed on the basis of half wave potentials measured by anodic oxidation by means of differential pulse voltammetry. The tricyclic hydroxamic acids 18 and 28 show only a weak inhibition of 5-lipoxygenase (5-LOX).

Crystallography, X-Ray↗
PubMed2006

Cardiac histones are substrates of histone deacetylase activity in hemorrhagic shock and resuscitation.

BACKGROUND: DNA transcription is regulated, in part, by acetylation of nuclear histones that are controlled by 2 groups of enzymes: histone deacetylases (HDAC) and histone acetyl transferases (HAT). Whether an imbalance in HDAC/HAT system plays a role in hemorrhage/resuscitation is unknown. The goals of this study were to determine whether hemorrhage results in deacetylation of cardiac histones and whether this can be corrected through the application of different resuscitation strategies or specific HDAC inhibitors. METHODS: In the first experiment, rats (n = 6 per group) were subjected to volume-controlled hemorrhage and resuscitated with racemic lactated Ringer's solution, L-lactated Ringer's solution, 7.5% hypertonic saline solution, ketone Ringer's solution, and pyruvate Ringer's solution. Control groups included no hemorrhage (sham) and hemorrhage with no resuscitation. In the second experiment (n = 5 per group), 3 HDAC inhibitors (valproic acid, trichostatin A, and suberoylanilide hydroxamic acid) were added to saline solution resuscitation. Heart tissue was collected at the end of resuscitation. Isolated subcellular protein fractions were used in Western blotting to analyze the patterns of total protein acetylation and histone acetylation specifically. HDAC and HAT activity was measured in tissue extracts. RESULTS: Hemorrhage led to partial histone deacetylation. Resuscitation resulted in protein hyperacetylation in nuclear fractions only. A detailed analysis of histones (on 10 acetylation sites) revealed that ketone Ringer's solution hyperacetylated histones H2B, H3, and H4. The addition of suberoylanilide hydroxamic acid hyperacetylated histones more effectively than other resuscitation strategies, presumably by direct inhibition of HDAC activity. CONCLUSION: Hemorrhage/resuscitation is associated with HDAC/HAT activity misbalance, and the acetylation status of cardiac histones is influenced by the choice of resuscitation strategy. Shock-induced changes can be reversed through the infusion of pharmacologic HDAC inhibitor, even when it is administered after the insult for a limited period of time.

Acetylation↗
PubMed2001

Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin.

Trichostatin A (TSA) and trapoxin (TPX) are potent inhibitors of histone deacetylases (HDACs). TSA is proposed to block the catalytic reaction by chelating a zinc ion in the active-site pocket through its hydroxamic acid group. On the other hand, the epoxyketone is suggested to be the functional group of TPX capable of alkylating the enzyme. We synthesized a novel TPX analogue containing a hydroxamic acid instead of the epoxyketone. The hybrid compound cyclic hydroxamic acid-containing peptide (CHAP) 1 inhibited HDAC1 at low nanomolar concentrations. The HDAC1 inhibition by CHAP1 was reversible as it was by TSA, in contrast to the irreversible inhibition by TPX. CHAP with an aliphatic chain length of five, which corresponded to that of acetylated lysine, was stronger than those with other lengths. These results suggest that TPX is a substrate mimic and that the replacement of the epoxyketone with the hydroxamic acid converted TPX to an inhibitor chelating the zinc like TSA. Interestingly, HDAC6, but not HDAC1 or HDAC4, was resistant to TPX and CHAP1, whereas TSA inhibited these HDACs to a similar extent. HDAC6 inhibition by TPX at a high concentration was reversible, probably because HDAC6 is not alkylated by TPX. We further synthesized the counterparts of all known naturally occurring cyclic tetrapeptides containing the epoxyketone. HDAC1 was highly sensitive to all these CHAPs much more than HDAC6, indicating that the structure of the cyclic tetrapeptide framework affects the target enzyme specificity. These results suggest that CHAP is a unique lead to develop isoform-specific HDAC inhibitors.

3T3 Cells↗
PubMed1987

Proteoglycan degradation by a chondrocyte metalloprotease. Effects of synthetic protease inhibitors.

Synthetic inhibitors of a chondrocyte metalloprotease (CMP) were assessed for potency. Proteoglycan core protein was used as substrate. The IC50 values were between 2 X 10(-6) and 7 X 10(-6) M for two types of inhibitors, thiol tripeptides and N-carboxyalkyl peptides. Hydroxamic acid peptides were more potent, with IC50 values of 3.2 X 10(-8) to 6.0 X 10(-8) M. These results confirm inhibitory concentrations reported using a proteoglycan-polyacrylamide bead assay. The slopes of the dose-response curves for the thiol compounds were steeper than the slopes for the other two types of compounds. All of the culture media tested inhibited CMP to some extent. Some media also interfered with inhibitor activity. In Ham's F10 nutrient medium, minimum CMP inhibition occurred, and all four hydroxamic acid peptides retained their activity for 1-2 days at 37 degrees. One thiol peptide compound assayed lost activity in 1 hr in thiocyanate-treated serum. All four hydroxamic acid peptides assayed retained activity in thiocyanate-treated serum after 3 days at 37 degrees. The hydroxamic acid peptides may provide a way to block endogenous CMP activity in vivo and to assess the role of CMP in normal and experimentally altered cartilage. They are more potent than other known CMP inhibitors. They retain activity in culture media and serum conditions used for in vivo and in vitro tests of CMP activity and toxicity.

Animals↗
PubMed2001

Histone deacetylase as a new target for cancer chemotherapy.

Trichostatin A (TSA) and trapoxin (TPX), inhibitors of the eukaryotic cell cycle and inducers of morphological reversion of transformed cells, inhibit histone deacetylase (HDAC) at nanomolar concentrations. Recently, FK228 (also known as FR901228 and depsipeptide) and MS-275. antitumor agents structurally unrelated to TSA, have been shown to be potent HDAC inhibitors. These inhibitors activate the expression of p21Waf1 in a p53-independent manner. Changes in the expression of regulators of the cell cycle, differentiation, and apoptosis with increased histone acetylation may be responsible for the cell cycle arrest and antitumor activity of HDAC inhibitors. TSA has been suggested to block the catalytic reaction by chelating a zinc ion in the active site pocket through its hydroxamic acid group. On the other hand, an epoxyketone has been suggested to be the functional group of TPX capable of alkylating the enzyme. We synthesized a novel TPX analogue containing a hydroxamic acid instead of the epoxyketone. The hybrid compound, called cyclic hydroxamic-acid-containing peptide 1 (CHAP1) inhibited HDAC at low nanomolar concentrations. The HDAC1 inhibition by CHAPI was reversible, as is that by TSA, in contrast to irreversible inhibition by TPX. Interestingly, HDAC6, but not HDAC1 or HDAC4, was resistant to TPX and CHAP1, while TSA inhibited these HDACs to a similar degree. CHAP31, the strongest HDAC inhibitor obtained from a variety of CHAP derivatives, exhibited antitumor activity in BDF1 mice bearing B16/BL6 tumor cells. These results suggest that CHAP31 is promising as a novel therapeutic agent for cancer treatment, and that CHAP may serve as a basis for new HDAC inhibitors and be useful for combinatorial synthesis and high-throughput screening.

Animals↗
PubMed2004

A bioinorganic perspective on matrix metalloproteinase inhibition.

The zinc-dependent enzymes known as matrix metalloproteinases (MMPs) are medicinal targets due to the activity of these enzymes associated with diseases such as cancer, heart disease, and arthritis. The development of most MMP inhibitors (MPIs) has followed a basic design formula: a peptidomimetic backbone is attached to a zinc-binding group (ZBG). MPI backbones have varied enormously and improved with increased knowledge of MMP structure and function while hydroxamic acids have been used as the ZBG in most inhibitors. The problems associated with hydroxamic acid and other current ZBGs have been identified; the incorporation of more potent and selective ZBGs for the active site zinc(II) ion is necessary to improve the development of second-generation inhibitors. Herein, we highlight ZBGs that have been proposed as alternatives to hydroxamic acids. In addition, techniques used to identify new ZBGs are also discussed. New insights from a bioinorganic approach using model complexes of the MMP active site are presented as tools in examining the mode of binding for various known and novel ZBGs. Novel computational methods are highlighted that allow for modeling the drug-protein interactions with non-hydroxamate inhibitors of MMPs. We suggest that significant efforts to augment ZBGs combined with the available information on inhibitor backbone design will accelerate the discovery of improved MPIs. Newly devised drug design methods will help to realize this proposal.

Animals↗