Aliphatic Hydroxamic Acids

Figure 9.5 SAR exploration of aliphatic hydroxamic acid HDACis.

Further work by the same group resulted in the identification of indole amides as an alternative capping group for aliphatic hydroxamic acids [31]. Starting from... 

Dihydroxygenzhydroxamic acid Secondary Aliphatic hydroxamic acids >800 mg/kg i.p. 6 0 1 ... 

R. erythropolis A4 " Aromatic and aliphatic nitriles Aromatic and aliphatic hydroxamic acids Bienz5tmatic S5mthesis of hydroxamic acids (chelators) NHase screening [92]... 

It may be noted that primary aliphatic amides are readily converted by hydro-xylamlne hydrochloride into hydroxamic acids, which may be detected by the addition of ferric chloride solution ... 

In the crystal structures, the inhibitors coordinate to the active site zinc and make a series of hydrogen bonds via their hydroxamic acid moiety. The hydroxamic acids are linked by a flexible spacer with bulky cap groups. The aromatic or aliphatic spacer participates in van der Waals interactions throughout the long charmel, whereas the terminal part of the inhibitor interacts with residues at the rim of HDAC. In general, the binding mode of the cocrystallized inhibitors TSA and SAHA is conserved among the different species and subtypes [35]. 

As already mentioned, the field of hydroxamic acid HDACis is extensive, therefore the next paragraphs are divided into sections depending on the nature of the group attached to the hydroxamic acid, including aliphatic, cinnamic, phenyl and heterocyclic hydroxamic acids. 

The HDAC inhibitors TSA and TPX (Fig. 2) have been utilized as structural leads in the early stages of the quest for new and more selective small molecule inhibitors of the HDAC enzyme family. In order to investigate the function of the individual HDAC members, Schreiber et al. synthesized a library of 7200 potential HDAC inhibitors based on the structural features of TSA and TPX [93]. The members of this library were prepared on solid support by means of split pool methods. The key characteristics of these compounds consist of a dioxane-containing capping region and a zinc binding motive, connected via an aliphatic chain. Three different zinc binders, i.e., carboxylic acid, o-aminoanilide and hydroxamic acid were used. 

Formation of hydroxamic acids via the reaction of the carbonyl group of aldehydes and a-oxo acids with the aromatic or aliphatic C-nitroso group belongs to the small number of nucleophilic reactions of the C-nitroso group. ... 

The hydroxamic acid test is also given by acid chlorides and some primary aliphatic amides which are readily converted by hydroxylamine hydrochloride into hydroxamic acids. Some esters, mainly of carbonic, carbamic, sulphuric and other inorganic acids, give only a yellow colour. 

Aliphatic nitroso compounds can be prepared from IV-alkylhydioxylamines oxidation widi bromine, chlorine or sodium hypochlorite in weakly acidic solution, reaction with potassium dichromate in acetic or sulfuric acid, and by oxidation widi yellow mercury(II) oxide in suspension in an organic solvent. Silver carbonate on Celite has also been used to prepare aliphatic nitroso compounds, such as ni-trosocyclohexane, in high yield from the corresponding hydroxylamines." Aqueous sodium periodate and tetraalkylanunonium periodates, which are soluble in organic solvents, are the reagents most commonly used for the oxidation of hydroxamic acids and IV-acylhydroxylamines to acylnitroso compounds... 

Hydroxamic acids (4, 202). This oxidant is preferred for oxidation of tri-methylsilylated amides to hydroxamic acids. Although the yields on oxidation of silylated secondary aliphatic amides with 1 are usually only moderate (15-40%), hydroxylation of acetanilides proceeds consistently in yields of 40-50%. The reaction is efficient for oxidation of benzoxazinones, for example, 2->3. The products are useful herbicides because of inhibition of auxin. 

Hydroxylamines usually react with acid chlorides to give mixtures of N-, O- and poly-acylated products. In contrast reaction of tris(trimethylsilyl)hydroxylamine (65) with aliphatic acid chlorides leads selectively under /V-monoacylation to the corresponding hydroxamic acids (66 equation 26). While di-phenylphosphinic chloride (68) is attacked by the oxygen of hydroxylamine to yield 0-(diphenylphos-phinyl)hydroxylamine (67 Scheme 13), A -(diphenylphosphinyl)hydroxylamine (69) can be obtained by treatment of diphenylphosphinic chloride with 0-trimethylsilylhydroxylamine followed by removal of the silyl blocking group (Scheme 13). 0-Acylation of arylhydroxylamines can be achieved with acyl cyanides. ... 

We next decided to study the effect on MMP-inhibitory potency of a fluoroalkyl group installed in a more distant position from the hydroxamic acid group, in order to better understand the unique stereoelectronic properties of fluoralkyl groups in a purely aliphatic position [39], For this purpose we chose as a model system a structurally simple class of hydroxamic acid inhibitors bearing an arylsulfone moiety at the P-position such as D (see Figure 4.5), which showed nanomolar inhibitory potency for MMP-2, MMP-3, and MMP-13 [40-42]. 

Fig. 4. The 220 MHz PMR spectra of deferriferrichrome (a) and alumichrome (b) dissolved in (CD3)2SO at about 45 °C (29). The lone peak at 9,60 ppm in (a) is assigned to the hydroxamic acid NOH resonance which is absent in (b). The rest of the peaks below and above 5 ppm are amide NH and aliphatic resonances, respectively. The sharp peak(s) at —2 ppm arises from the acetyl methyl groups. Glycyl and ornithyl NH resonances are readily distinguished by their multiplet character as the former are triplets and the latter doublets. Arrows connect resonances showing vicinal spin-spin coupling interactions, which allow their assignment to the a, / , etc. protons. The resonances are referred to internal tetramethylsilane...

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