Free hydroxamic acids

Hydroxumie acids. Oxidation of N-trimethylsilylamtdes (I, prepared by the reaction of a secondary amide with hexamethyldisilazane) with the MoOvMMPT complex in methylene chloride at room temperature for several hours np to several days affords dioxomolybdenum complexes (2) in moderate yields (15-40%). The free hydroxamic acids (3) are Hbcrated by treatment of (2) with ethylenediaminetetraacetic acid (EDTA). 

Nucleophilic Reactions. M,C)-Bis(trimethylsilyl)hydroxyl-amine is a protected, lipophilic form of hydroxylamine. It reacts with a variety of electrophiles predominantly by attack on the nitrogen nucleophilic center. Reaction with acid chlorides (1 equiv) in the presence of triethylamine gives M<9-bis(trimethylsilyl)-hydroxamic acids by iV-acylation. A related reagent, tris(tri-methylsilyl)hydroxylamine, gives the same product in high yields, also by iV-acylation. Hydrolysis gives the free hydroxamic acids, whereas thermal fragmentation affords isocyanates (eq 1). ... 

The previous synthesis can also be performed in water from both W-methoxybenzamides and free hydroxamic acid. In water the best catalytic system was found to be [RuCl2(p-cymene)]2 associated with K02CMes (30 mol%) and the reaction takes place at 60°C [(Eq. 93)] [182]. 

The C-H bonds that are not stericaUy hindered by a neighbouring substituent in meta-position, unless they are electron-withdrawing groups, provide better reactivity. This reaction applied to free hydroxamic acid leads to isoquinolones but under slightly more drastic conditions at 60-100°C [(Eq. 94)] [182]. 

The same reaction can also be performed with water as solvent medium by the catalytic system of [RuCl2(p-cymene)]2 associated with K02CMes (30mol%) at 60 "C [32]. Free hydroxamic acid appeared also suitable for this annulation under... 

In addition to the general usefulness of this class of compounds, the popularity of this chemistry is largely due to the facile preparation of the starting materials (Scheme 7). The most straightforward method of preparation of Barton esters of types I to IV is acylation by activation of the corresponding carboxylic acid (paths A and B). Accordingly, the hydroxamic acid sodium salt can be O-acylated with the acyl chlorides or, alternatively, the free hydroxamic acid can be condensed with primary carboxylic acids in the presence of N,W -dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP). Likewise, condensation of the free thiohydroxamic acid or the corresponding sodium salt with the mixed anhydride formed from the acid and isobutyl chloroformate in the presence of N-methylmorpholine has proven to... 

A soln. of 0-benzoyl benzohydroxamic acid in tetrahydrofuran added with stirring and cooling to a soln. of LiAlH4 in the same solvent, and refluxed 15 hrs. -y benzylamine (Y 80%) and benzyl alcohol (Y 90%).— Reduction of acyl hydroxamates is smoother and gives better yields than reduction of the free hydroxamic acids. F. e. s. F. Winternitz and G. Wlotzka, Bl. 1960, 509. 

NITRILE OXIDES. Nitrile oxides are a well known class of compds represented by R.C N- 0, and are usually prepd by treating hydroxamic acid chlorides with a mild alkali, thus eliminating HQ (Ref 2). Wieland (Refs 1 3) was responsible for the first isolation of free nitrile oxides. These compds are somewhat unstable, showing a marked tendency to dimerize to (he corresponding furoxanes (1,3-dipolar addition) (Refs 2 3). The nitrile oxides add to a considerable number of carbenes, as benzonitrUe oxide (for example) to a large number of olefins in ether at 20° (Ref 3)... 

A combination first coordination shell-second coordination shell based recognition BLM transport system was devised, including active transport (200). This is based on a labile dihydroxamic acid system, including alcaligin, and a free lysine hydroxamic acid ligand capable of ternary complex formation to... 

Since the analogous peroxides usually decompose by a free radical mechanism, it is noteworthy that this hydroxamic acid is not sensitive to the action of free radicals from anisoyl peroxide. A radical chain mechanism like that shown below can therefore be ruled out for this compound. 

Hydroxamic acid derivatives, which belong to a new class of NO donors, have been shown to inhibit the matrix metalloproteinases (MMPs) [112]. MMPs are a family of zinc-dependent endopeptidases, which play a critical role in multiple steps in the metastatic cascade and facilitate neoangiogenesis. Numerous hydroxamic acids, such as marimastat, have been developed, that bind the zinc atom in the active catalytic domain of MMPs. During a randomized Phase III trial, comparing marimastat with placebo in patients with metastatic breast cancer, marimastat was not associated with an improvement in progression-free survival or overall survival. Other studies also indicated no benefit for MMP inhibitors when used either in combination with chemotherapy or sequentially after first-line chemotherapy in a variety of cancers [113]. Currently, many pharmaceutical companies have suspended clinical development of this kind of agent. 

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. 

Hydroxamic acids, possessing a free NH group" (e.g. 46), as weU as iV-hydroxy sulfonamides" "6 also undergo addition to an activated double bond of type 47 (equation 31) under basic catalysis. 

In 2003, Devocelle and colleagues reported a convenient two-step procedure for the parallel synthesis of hydroxamic acids (or O-protected hydroxamic acids 207) from carboxylic acids and hydroxylamine. It involves the formation of a polymer-bound HOBt active ester 206 from 204 and the acid 205 and subsequent reaction with O-protected or free hydroxylamine (Scheme 89). The use of free hydroxylamine leads to increased yields while maintaining high purities. Recycling of the exhausted resin 204 to prodnce the same or a different hydroxamic acid has been achieved by a three-step protocol, which is easily amenable to automation and cost-economical. 

There is some evidence that the form of the chemical carcinogen that ultimately reacts with cellular macromolecules must contain a reactive electrophilic center, that is. an electron-deficient atom that can attack the numerous electron-rich centers in polynucleotides and proteins. As examples, significant electrophilic centers include free radicals, carbonium ions, epoxides, the nitrogen in esters of hydroxylamines and hydroxamic acids, and some metal cations. It is believed that carcinogens, which in themselves are not electrophiles, are metabolized to electrophilic derivatives that then become the ultimate" carcinogens. 

This method is based on the fact that only esters, but not free carboxylic acids, react with hydroxylamine to form hydroxamic acids, which can be determined colorimetrically as complex with ferric chloride (8). The method—in contrast to most other procedures—measures the concentration of remaining substrate instead of products of hydrolysis. It also requires purified enzymes because of the interference of colored contaminants in the colorimetric measurements. 

The yield of radiolysis products depends strongly on the presence of an aqueous phase in the system, and on its composition. The presence of water and nitric acid in the solvent produces additional free radicals by radiolysis (14, 302, 303), leading to functionalized compounds of extractants and diluents (304). In the case of alkanes, specific compounds like nitroparaffins, alcohols, hydroxamic acids, and nitronic acids have been identified (21, 43, 51). Taharaoui and Morris have summarized the results published in this held (79). 

Growth of Fusariutn sp. at low iron concentration causes the accumulation of a variety of hydroxamic acids of which one has been characterized and named fusarinine, or NS-( s-5-hydroxy-3-methylpent-2-enoyl)-NS-hydroxy-L-ornithine (38). The cis configuration in the unsaturated acyl substituent accounts for the extreme acid lability of the hydroxamic acid bond. Fusarinine is the amino acid unit, bearing the hydroxamic acid linkage, present in ferrirhodin. The characterization of fusarinine has important implications for the biosynthesis of the ferrichrome group for it indicates that the hydroxamic acid bond is inserted at the free amino, acid, rather than at the peptide level. 

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