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A series of acyclic hydroxamic acids harboring strategically placed alpha-arylsulfonamido and thioether groups was synthesized and found to be potent inhibitors of various MMPs. An unprecedented cleavage of t-butyl hydroxamates to hydroxamic acids was found.
Energy production in bloodstream forms of African trypanosomes of the genus Trypanosoma involves two pathways unique to the parasite and which can be blocked by a combination of salicylhydroxamic acid (SHAM) and glycerol. Although this leads to rapid parasite destruction both in vitro and in vivo, the toxicity of SHAM precludes practical use of SHAM/glycerol as a therapeutic regimen. Based on our hypothesis that SHAM operates by interfering with ubiquinone, we attempted to develop this approach by synthesizing and screening a series of hydroxamic acids which more closely resemble ubiquinone: the p-n-alkyloxybenzhydroxamic acids. We also examined a variety of mono-, di- and trisubstituted benzhydroxamic acids together with a selected group of secondary heterocyclic hydroxamic acids. We found an increase in activity of the p-n-alkyloxy compounds with increasing chain length up to 12 carbon atoms with longer chains offering little advantage. The most active compound, p-n-tetradecyloxybenzhydroxamic acid, had an apparent Ki of 0.43 microM indicating a specific activity 70 times greater than SHAM. Although this represents a vast improvement, the low water solubility of these compounds reduces their bioavailability to the point where they are not practical substitutes for SHAM. Consequently, improvement in the SHAM/glycerol approach to chemotherapy appears to lie with improving solubility by altering lipophilicity of the alkyl side chain.
Histone deacetylase inhibitors are potent inducers of growth arrest, differentiation, or apoptotic cell death in a variety of transformed cells in culture and in tumor bearing animals. Histone deacetylases and the family of histone acetyl transferases are involved in determining the acetylation of histones, which play a role in regulation of gene expression. Radiograph crystallographic studies reveal that the histone deacetylase inhibitors, suberoylanilide hydroxamic acid and trichostatin A, fit into the catalytic site of histone deacetylase, which has a tubular structure with a zinc atom at its base. The hydroxamic acid moiety of the inhibitor binds to the zinc. Histone deacetylase inhibitors cause acetylated histones to accumulate in both tumor and peripheral circulating mononuclear cells. Accumulation of acetylated histones has been used as a marker of the biologic activity of the agents. Hydroxamic acid-based histone deacetylase inhibitors limit tumor cell growth in animals with little or no toxicity. These compounds act selectively on genes, altering the transcription of only approximately 2% of expressed genes in cultured tumor cells. A number of proteins other than histones are substrates for histone deacetylases. The role that these other targets play in histone deacetylase inducement of cell growth arrest, differentiation, or apoptotic cell death is not known. This review summarizes the characteristics of a variety of inhibitors of histone deacetylases and their effects on transformed cells in culture and tumor growth in animal models. Several structurally different histone deacetylase inhibitors are in phase I or II clinical trials in patients with cancers.
A series of hydroxamic acids has been prepared as potential inhibitors of glutamate carboxypeptidase II (GCP II). Compounds based on a P1' residue (primed-side inhibitors) were more potent than those based on a P1 group (unprimed-side inhibitors). Inhibitory potency of the primed-side GCP II inhibitors was found to be dependent on the number of methylene units between the hydroxamate group and pentanedioic acid. Succinyl hydroxamic acid derivative, 2-(hydroxycarbamoylmethyl)pentanedioic acid, is the most potent GCP II inhibitor with an IC(50) value of 220nM. The comparison of the results to those of other classes of GCP II inhibitors as well as hydroxamate-based MMP inhibitors provides further insight into the structure-activity relationships of GCP II inhibition.
Histone deacetylase inhibitors have generated significant interest as anti-cancer agents due to their ability to cause growth arrest, terminal differentiation and/ or apoptosis in carcinoma cells. Abbott entered this area after the serendipitous discovery of the biaryl hydroxamate A-161906 in a TGF beta mimetic screen and the subsequent identification of this compound as an inhibitor of selected HDACs. The complex biology of these enzymes became evident when cloning and expression of the HDACs demonstrated that they were present as multiprotein and, in some cases, multi-HDAC containing complexes in their active forms. This discovery suggested that any selectivity determinations would have to be considered in the context of these multi-protein/HDAC complexes. However, siRNA gene knockdown studies did demonstrate that reduction of the Class I HDACs resulted in a phenotype similar to that observed with small molecule HDAC inhibitors. Evaluation of the Abbott small molecule HDAC inhibitors utilized a Class I HDAC (HDAC 1/2) preparation and antiproliferation assays using HT1080 fibrosarcoma and MDA435 breast carcinoma cells. Characterization of several series of hydroxamic acids indicated that while many of these analogs possessed potent enzymatic and cellular activity, in general these compounds had unacceptable pharmacokinetic profiles and marginal antitumor effects. Replacement of the potentially labile hydroxamic acid moiety with a trifluoromethyl ketone or a ketooxazole gave measurable HDAC potency but only modest cellular and in vivo activity. However, hydroxamate replacement with an alpha-ketoamide moiety provided potent HDAC inhibitors (IC(50) values as low as 3 nM) with excellent cellular activity (IC50 values < 0.2 microM) and measurable anti-tumor activity in a flank tumor growth model.
The adenylyl cyclases (ACs) are a family of intracellular enzymes associated with signal transduction by virtue of their ability to convert ATP to cAMP. The catalytic mechanism of this transformation proceeds through initial binding of ATP to the so-called purine binding site (P-site) of the enzyme followed by metal-mediated cyclization with loss of pyrophosphate. Crystallographic analysis of ACs with known inhibitors reveals the presence of two metals in the active site. Presently, nine isoforms of adenylyl cyclase are known, and unique isoform combinations are expressed in a tissue-specific manner. The development of isoform-specific inhibitors of adenylyl cyclase may prove to be a useful strategy toward the design of unique signal transduction inhibitors. To develop novel AC inhibitors, we have chosen an approach to inhibitor design utilizing an adenine ring system joined to a metal-coordinating hydroxamic acid via various linkers. Previous work in our group has validated this approach and identified novel inhibitors that possess an adenine ring joined to a metal-coordinating hydroxamic acid through flexible acyclic linkers (Levy, D. E., et al. Bioorg. Med. Chem. Lett. 2002, 12, 3085-3088). Subsequent studies have focused on the introduction of conformational restrictions into the tether of the inhibitors with the goal of increasing potency (Levy, D. E., et al. Bioorg. Med. Chem. Lett. 2002, 12, 3089-3092). Building upon the favorable spatial positioning of the adenine and hydroxamate groups coupled with potentially favorable entropic factors, the unit joining the carbocycle to the hydroxamate was explored further and a stereochemical-based SAR was elucidated, leading to a new series of highly potent AC inhibitors.
Leukotriene (LT) A4 hydrolase/aminopeptidase is a bifunctional zinc enzyme that catalyzes the final step in the biosynthesis of LTB4, a potent chemoattractant and immune modulating lipid mediator. Here, we report a high-resolution crystal structure of LTA4 hydrolase in complex with captopril, a classical inhibitor of the zinc peptidase angiotensin-converting enzyme. Captopril makes few interactions with the protein, but its free thiol group is bound to the zinc, apparently accounting for most of its inhibitory action on LTA4 hydrolase. In addition, we have determined the structures of LTA4 hydrolase in complex with two selective tight-binding inhibitors, a thioamine and a hydroxamic acid. Their common benzyloxyphenyl tail, designed to mimic the carbon backbone of LTA4, binds into a narrow hydrophobic cavity in the protein. The free hydroxyl group of the hydroxamic acid makes a suboptimal, monodentate complex with the zinc, and strategies for improved inhibitor design can be deduced from the structure. Taken together, the three crystal structures provide the molecular basis for the divergent pharmacological profiles of LTA4 hydrolase inhibitors. Moreover, they help define the binding pocket for the fatty acid-derived epoxide LTA4 as well as the subsites for a tripeptide substrate, which in turn have important implications for the molecular mechanisms of enzyme catalyses.
The synthesis and characterization of hydroxamic acid containing single-chain and TRIS-assembled (where TRIS is tris(carboxyethoxymethyl)aminomethane) collagen mimetics are reported. We have engineered an Fe(III)-binding domain by placing a hydroxamic acid group at the C termini of collagen mimetic chains composed of the Gly-Pro-NLeu sequence. The circular dichroism spectra and thermal denaturation studies show an enhancement in triple-helical thermal stability upon the addition of Fe(III) for the TRIS-assembled structure. No triple-helical structure was detected for the single-chain collagen mimetic. From the absorbance shown in the UV-vis spectra, we believe that the thermal stabilization of the triple helix is the direct result of a coordination complex between Fe(III) and the hydroxamate groups tethered to the C termini of the collagen mimetic peptide chains.
Due to their involvement in many pathological conditions, matrix metalloproteinases (MMPs), are very attractive therapeutic targets. Our study focuses on one of them, MMP-2, which is involved in tumor progression and metastasis. Recently, the solution structure of the catalytic domain of MMP-2 complexed with a hydroxamic acid inhibitor (SC-74020) was published by Feng et al. Using the Hanessian group published binding affinity data and the structure published by Feng as a basis, we have built a binding affinity model by targeting the S(2)' pocket of the enzyme with a set of nine alpha-N-sulfonylamino hydroxamic acid derivatives. Two binding geometries of each ligand have been generated corresponding to two binding modes denoted A and B, respectively, of which the first one is targeting the S(2)' pocket and the second one the S(1) pocket. For the binding affinity model developed for mode A the computed activities show a rmsd of 0.583 kcal/mol as compared with the experimental data, and a correlation coefficient r(2) of 0.779, while in the case of the binding mode B a rmsd of 0.834 kcal/mol and correlation coefficient r(2) of 0.500, respectively, were obtained. In conclusion, our data suggest a higher probability for the Phe(76) gated S(2)' open form pocket to accommodate the substituent alpha versus the wide solvent exposed S(1) subsite, probability which some research groups could have overlooked due to extensive use in their calculations of non revealing S(2)' pocket open state crystallographic structures instead of NMR ones.
A series of N-benzoyl 4-aminobutyric acid hydroxamate analogs were synthesized and evaluated as matrix metalloproteinase inhibitors. Synthetic work was focused on the chemical modification of the 4-aminobutyric acid part using easily available starting materials. As such, chemical modification was carried out using commercially available starting materials such as 4-aminobutyric acid, (+)- and (-)-malic acid, and D- and L-glutamic acid derivatives. Among the compounds tested, N-[4-(benzofuran-2-yl)benzoyl] 4-amino-4S-hydroxymethylbutyric acid hydroxamates derived from L-glutamic acid demonstrated more potent inhibitory activity against MMP-2 and MMP-9 compared with the corresponding 2S-hydroxy analogs or 3S-hydroxy analogs, respectively, which were derived from (-)-malic acid. Structure-activity relationship study is presented.
We examined the pharmacokinetics of KIH-802, potassium 2-nitroimidazole-1-acetohydroxamate, using its radioisotope-labelled compound and the acute toxicity in mice. We discovered that the concentration of KIH-802 was very low in the brain and its LD50 was nearly half the value of that of MISO. We also present here new 2-nitroimidazole radiosensitizers/chemical modifiers (KIN-804, 811, 831, 841, 844, 821, 823 and 824) designed to enhance their sensitizing ability intensely by substituting various biologically active groups, such as hydroxamic acids and oximes, with moderate lipophilicity to the aromatic ring, if necessary, through some spacers. The sensitizing effects of all compounds were estimated to be almost equal to or better than that of MISO. The results of their toxicities shows that new hydroxamates KIN-804 and 831 are less toxic than KIH-802 and MISO. Their in vitro enhancement ratios are 2.00 and 1.75, respectively, compared with those of KIH-802, MISO and SR-2508, 1.77, 1.72 and 1.72, respectively, at each dose of 1 mM for EMT6/KU single cell. We concluded that they may be superior radiosensitizers of hydroxamic acid analogues to KIH-802.
Jack bean urease [EC 3.5.1.5] was modified with diazonium-1H-tetrazole (DHT). Reaction of DHT with the enzyme produced a characteristic absorption peak at 320 nm and led to complete loss of the enzymatic activity at a low concentration of DHT. Amino acid analysis of DHT-modified urease showed that only cysteine residues reacted with the reagent and other amino acid residues such as tyrosine, histidine, and lysine did not. The enzymatic activity was protected against DHT-inactivation by the addition of substrate. On the other hand, when the cysteine residues were modified with DHT, the enzyme was not converted to polymeric forms. Furthermore, the binding ability of urease with hydroxamic acid, a specific urease inhibitor, was virtually unaffected by DHT-inactivation. These results indicate that cysteine residues are specifically modified by DHT with concomitant loss of enzymatic activity and polymerization ability, but are not essential for the binding of hydroxamic acid to the enzyme.
A comparison of the molecular parameters of gamma-aminobutyric acid (GABA), the hydroxamic acid of GABA (HAGABA), and muscimol has been made using structural data and partial charges from the AM1 semiempirical quantum mechanical method. It was concluded that HAGABA was more closely related to GABA than muscimol.
Peptide mimetics are of considerable interest as bioactive agents and drugs. C-terminally modified peptide mimetics are of particular interest given the synthetic versatility of the carboxyl group and its derivatives. A general approach to C-terminally modified peptide mimetics, based on a urethane attachment strategy and amino acid t-butyl ester-based N-to-C peptide synthesis, is described. This approach is compatible with the reaction conditions generally employed for solution-phase peptide mimetic synthesis. To develop and demonstrate this approach, it was employed for the solid-phase synthesis of peptide trifluoromethyl ketones, peptide boronic acids, and peptide hydroxamic acids. The development of a versatile general approach to C-terminally modified peptides using readily available starting materials provides a basis for the combinatorial and parallel solid-phase synthesis of these peptide mimetic classes for bioactive agent screening and also provides a basis for the further development of solid-phase C-terminal functional group elaboration strategies.
BACKGROUND & AIMS: Recently described genome-wide approaches robustly detect many candidate genes that are regulated by DNA methylation, but many of these genes do not represent important targets for functional inactivation. Here we used a microarray-based strategy to identify biologically relevant genes associated with epigenetic silencing in pancreatic cancer. METHODS: We compared information from differential gene expression analysis with the transcriptional responses to epigenetic modifiers. RESULTS: Using this approach, we identified 7 novel targets for aberrant methylation in pancreatic cancer. One of the genes identified, RELN (Reelin), a key regulator of neuronal migration, is frequently silenced in pancreatic cancers, as are several of its downstream mediators. Importantly, small interfering RNA-mediated knockdown of RELN in pancreatic cancer cells that retain RELN expression resulted in greatly enhanced cell motility, invasiveness, and colony-forming ability. Increased cell motility was also induced by knockdown of downstream components of the RELN pathway, including ApoER2, VLDLR, and DAB1. Treatment of pancreatic cancer cells with histone deacetylase inhibitors, valproic acid and suberoylanilide hydroxamic acid, restored the expression of RELN and DAB1 and markedly inhibited their migration. CONCLUSIONS: The high prevalence of the silencing of RELN pathway components and its reversal by histone deacetylase inhibitors suggest the importance of this pathway as a diagnostic and therapeutic target for pancreatic cancer.
The structures of propioxatins A (C17H29N3O6) and B (C18H31N3O6), new enkephalinase B inhibitors produced by Kitasatosporia setae SANK 60684, were determined. Both propioxatins consist of N-acyl-L-prolyl-L-valine. N-Acyl moieties of propioxatins A and B were alpha-propyl and alpha-isobutyl succinic acid beta-hydroxamic acid, respectively.
Representative amino acids, carboxylic acids, a ketone, hydroxamic acids, 3-hydroxypyridinones and a linear catecholcarboxyamide were tested in vitro to estimate their aluminum (Al) chelation potential. Their ability to solubilize Al from insoluble Al borate in a previously described octanol/aqueous (o/a) system was tested. Salicylhydroxamic acid, rhodotorulic acid, the 3-hydroxypyridin-4-ones and a sulfonated linear polycatecholcarboxamide significantly increased solubilized Al, suggesting Al chelation potential. Some of the above compounds and some compounds previously shown to solubilize Al in the o/a system were tested for their ability to mobilize Al from the Al plasma binding protein transferrin. Chelators solubilizing Al in the o/a system were comparably effective in mobilizing Al from transferrin, supporting the utility of the o/a system as a screening method. The o/a distribution coefficient of each chelator was determined, when possible, to assess its hydrophilicity. When compared with the suggested desirable hydrophilicity of effective chelators, the o/a distribution coefficient of many of the 3-hydroxypyridin-4-ones and a sulfonated linear polycatecholcarboxamide suggest that they might be able to chelate intracellular Al. The o/a distribution coefficient of each Al-chelator complex was determined, when possible, to predict the likelihood of redistribution within or excretion from the intact animal of this complex. Complexation of chelators with Al usually increased chelator hydrophilicity. The results suggest several compounds that warrant further investigation as potential alternatives to desferrioxamine in the treatment of Al accumulation and toxicity.
2-Cyano-6-alkylthio- and 6-phenylthiopyrazines were prepared from 2-cyano-6-chloropyrazine (CCP) in the reaction with mercaptans. By the transformation of the -CN group the corresponding amides, thioamides, amidoximes, acids, esters and hydroxamic acids and hydrazides were obtained. The oxidation of sulfur in the above mentioned compounds led to sulfoxy- and sulfonyl derivatives. In the screening for antituberculous activity compounds 30 and 42 showed the greatest activity (MIC = 31.2 microgram/cm3) against H37Rv strain and compund 8 so did against saprophytic ATCC 607 strain. The compounds with 6-benzylthio grouping were more active against ethionamide, isoniazide and capreomycine resistant strains.