Hydroxamic acids Subject

Replacement of the hydroxamic acid moiety of SAHA by an alternative chelator has been the subject of several studies. Suzuki and Miyata et al. have shown that replacement of the hydroxamic acid of SAHA with a free thiol moiety does not affect the enzymatic HDAC inhibition capability of the compound [57]. Furthermore, replacement of the hydroxamic acid of SAHA by a trifluoromethyl ketone was investigated by Frey et al. (Fig. 8) [58]. The activated ketone is readily hydrated to form the vicinal diol, a structural feature known to bind to zinc-dependent proteases [59]. The in vitro evaluation was done on a partially purified HDAC preparation consisting largely of HDAC 1 and HDAC2 [60], exhibiting an IC50 of 6.7 xM. 

The first term of the rate law requires acid-catalyzed decomposition of the conjugated acid of the ester. This term predominates only under strongly acidic conditions. It has not been investigated in detail, but the major product of the acid catalyzed reaction is the corresponding hydroxylamine. The second term predominates under neutral to mildly acidic conditions. This term is consistent with uncatalyzed heterolysis of the N—O bond of the neutral ester to generate a heteroaryinitrenium ion. " The rate law is more complicated than that for reactive esters of carbocyclic hydroxylamines or hydroxamic acids that show pH-independent decomposition over a wide pH range. The kinetic behavior of the heterocyclic esters is caused by protonation of a pyridyl or imidazolyl N under mildly acidic conditions. The protonated substrates are not subject to spontaneous uncatalyzed decomposition, so decreases under acidic conditions until acid-catalyzed... 

Hydroxamic acids have been the subject of six papers 43 90 94 Earlier the operation of the a-effect in the reaction of p-nitrophcnyl acetate with benzohydroxamates in aqueous MeCN was discussed.43 The conformational behaviour of series of mono- (105) and di-hydroxamic acids (106) in MeOH, DMSO, and chloroform and in the solid state has been examined witii IR and NMR spectroscopy.90 X-ray crystal structure determinations of (105 X = Me, R = Me) and die monohydrate of glutarodihydroxamic acid (106 n = 3, R = H) together widi ab initio MO calculations for several hydrated and non-hydrated acids have been performed. The cis-Z conformation of the hydroxamate groups is preferentially stabilized by H-bonding witii water. 

The entire subject has been reviewed in detail several times.32,56,57,65 Recently, a new adsorptive method for the isolation of DIMBOA has been reported.49 The impact of benzoxazinoids on the western corn rootworm (Diabrotica virgifera LeConte) development has been studied.17 The allocation of a hydroxamic acid and biomass during vegetative development of rye has been investigated.27 Effects of benzoxazinoids from maize on survival and fecundity of aphids have been explored.13 DIMBOA concentrations have been measured in various isolines of wheat and corresponding plant introduction lines.55 The variation of the content of several benzoxazinoids in relation to the age and plant organ has been determined in maize plants.12... 

Diels-Alder precursor hydroxamic acid 174 (prepared by a multistep reaction) was subjected to subsequent oxidation and cycloaddition to provide bicyclic intermediates 175, which underwent ring cleavage by reduction with Na(Hg) amalgam, affording the eight-membered heterocycle 176 (Scheme 74 <2004JOC3025>). 

The first synthesis (left pathway) affording DIBOA started from a protected 2-nitrophenoI [109], The need to handle a free donor-substituted arylhydroxylamine reduces the yield distinctly and is a serious disadvantage. The second synthesis (middle left pathway), subject of a patent issued in 1975 to Hoffman-La Roche, is also starting from an appropriate ortho-suhstituted nitrobenzene [110]. In both syntheses the hydroxamic acid is generated by reductive cyclisation and the hemiacetal by hydrolysis of a chloride precursor. However, only the second procedure is applicable to the synthesis of the 7-methoxy compound DIMBOA. Therefore, this principle has later been developed further. The strategy of the third synthesis (middle right pathway) is different [111]. After alkaline cyclisation of the dichloroacetamide precursor to the hemiacetal unit the hydroxamic acid is obtained by oxidation of the... 

Antonis (A3, A5) has presented an automated colorimetric procedure for the determination of acyl esters in serum lipid extracts, based on his manual method (A2). The ester groups are subjected to alkaline hy-droxylaminolysis to form hydroxamic acids, which react with ferric ion to form highly colored chelates. 

The route developed by Fowler and his associates (287) involved an ingenious application of the aza-Cope rearrangement, in which the bridged hydroxamic acid derivative 468, prepared as shown in Scheme 48, was subjected to flash vacuum thermolysis. The product, the enol ether 469, was not isolated but immediately hydrolyzed to the ketone 470, which was then hydrogenated and cyclized to the racemic ketone 466. This appears to be the first application of the aza-Cope rearrangement in synthetic chemistry, since the reaction is normally not thermodynamically favored when C-1 is replaced by nitrogen. However, it is clearly successful when the nitrogen is acylated, as in the present example. 

For this reason, we consider it hardly possible to cite all of the publications. Let us focus only on the following examples. Hydroxamic acids have already been for a long time subject of the classical analytical chemistry. In [71], the possibility of using these compounds in flotation of rare-earth minerals is shown. It has been concluded that on a mineral surface cerium chelates are formed. Besides, chemisorption is accompanied by a physical multilayer adsorption of hydroxamic acid derivatives formed by reaction with cations in the water phase. A number of chelate-forming compounds including hydroxamic acids has been tested in flotation of niobium ores [72]. The best results are obtained when using alkyl phosphonic acids. Chemisorption mechanism and the structure of the surface compounds are established by spectroscopic methods. 

Oximes, a-oximinoketones, and a-hydroxyoximes react with phenylacetic acid in the presence of dicyclohexylcarbodiimide to form the oximino ester. At pH 5 and room temperature, H20-soluble carbodiimides convert hydroxamic acids to amines 7, Cyanooldehydes and -ketones are attainable by conversion of olefins to a-dimethylamino oximes and subjecting these to a Beckmann fragmentation ... 

The preparation of chelating resins is still an area of active research, so it cannot be discussed in detail in the limited scope of this chapter. However, let us consider one example to illustrate the technique in which a hydroxamic acid group has been introduced into the polymer matrix. In terpolymerization of styrene, divinyl benzene, and acrylic acid, the final polymer is a network resin with carboxylic acid groups on the chain (represented by [P]—COOH) [16]. This polymer is subjected to the following modifications ... 

NO-donors. In contrast, the effect of aceto-HX on B. subtilis subjected to oxidative stress is similar to that of HNO. SAHA, but not valproic acid lacking the hydroxamate moiety, enhances the radiosensitization of hypoxic tumor cells in vitro. This effect might also involve its abihty to serve as a NO-donor. It is concluded that HXs, which are HNO-donors under oxidizing environment, might be considered as NO-donors if HNO conversion into NO competes with its reaction with potential biological targets such as thiols and metalloproteins. 

Identification of the site of hydroxamate incorporation. To identify which amino acids were involved in the incorporation of hydroxylamine and the concomitant loss of the enzyme activity, all modified pepsins containing from 1.2 to 3.8 mole of hydroxamate per mole of pepsin (Table I) were subjected to Lossen rearrangement, followed by acid hydrolysis. All samples contained 2,3-diamino-propionic acid, but no 2,4-diaminobutyric acid was found using the amino acid analyzer. Thus, the PTFS-pepsin intermediates trapped with hydroxylamine must have been formed at the B-carboxyl groups of aspartate residues and glutamate residues were not involved. 

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