Hydroxamate model

Klotz etal.U9, l2° asserted that polymers from polyethylenimine reacted with chloromethylimidazole and dodecyliodide were excellent models for hydrolase. 70 [PEI-D(10%)-Im(l 5%)] catalyzed the hydrolyses of PNPA 270 times faster than imidazole itself. The authors also found that lauroylated polyethylenimine containing hydroxamate and imidazole groups, 71 [PEI-HA(8%)-L(8%)-Im(6.6%)], had a high efficiency in hydrolyses, i. e. 310 times that of imidazole. 

Researchers at Combio and Arpida have reported a series of isoxazole-3-hydroxamic acids as PDF inhibitors [109], Molecular modelling studies predict that the aryl substituent of isoxazole (37) binds into the SF pocket and that the oxygen atom of the isoxazole is involved in a H-bonding interaction with Ile-44 in E. coli PDF, similar to the PF carbonyl of actinonin. None of the inhibitors reported has sub-micromolar inhibitory activity against E. coli or S. aureus PDF. Not surprisingly, these moderately active inhibitors also lack antibacterial activity. 

Fe(III) displacement of Al(III), Ga(III), or In(III) from their respective complexes with these tripodal ligands, have been determined. The M(III)-by-Fe(III) displacement processes are controlled by the ease of dissociation of Al(III), Ga(III), or In(III) Fe(III) may in turn be displaced from these complexes by edta (removal from the two non-equivalent sites gives rise to an appropriate kinetic pattern) (343). Kinetics and mechanism of a catalytic chloride ion effect on the dissociation of model siderophore-hydroxamate iron(III) complexes chloride and, to lesser extents, bromide and nitrate, catalyze ligand dissociation through transient coordination of the added anion to the iron (344). A catechol derivative of desferrioxamine has been found to remove iron from transferrin about 100 times faster than desferrioxamine itself it forms a significantly more stable product with Fe3+ (345). 

Since the identification of hydroxamic acids as potent bidentate ZBGs, an enormous range of hydroxamic acid inhibitors based on this model has been developed and is described in numerous reviews and therefore will not be dealt with in depth here [17]. Instead, the focus of this report will be on efforts to improve on these "1st generation" inhibitors, specifically to improve biological and physicochemical characteristics, such as pharmacokinetics and bioavailability and to achieve isoform selectivity. 

ABC transporters involved in the uptake of siderophores, haem, and vitamin B]2 are widely conserved in bacteria and Archaea (see Figure 10). Very few species lack representatives of the siderophore family transporters. These species are mainly intracellular parasites whose metabolism is closely coupled to the metabolism of their hosts (e.g. mycoplasma), or bacteria with no need for iron (e.g. lactobacilli). In many cases, several systems of this transporter family can be detected in a single species, thus allowing the use of structurally different chelators. Most systems were exclusively identified by sequence data analysis, some were biochemically characterised, and their substrate specificity was determined. However, only very few systems have been studied in detail. At present, the best-characterised ABC transporters of this type are the fhuBCD and the btuCDF systems of E. coli, which might serve as model systems of the siderophore family. Therefore, in the following sections, this report will mainly focus on the components that mediate ferric hydroxamate uptake (fhu) and vitamin B12 uptake (htu). 

Trispyrazolylborates are models for tris-histidine active sites in zinc enzymes, e.g., the matrix metalloproteinases involved in breakdown of extracellular matrices. Inhibition of these metalloproteinases may prove valuable in the treatment of, inter alios, cancer and arthritis, so efforts are being made to find appropriate ligands to block the zinc active site. The search has recently moved on from hydroxamates to hydroxypyridinones - l-hydroxy-2-pyridinone is a cyclic analogue of hydroxamic acid. As reported in Section II.B.2 earlier, hydroxypyridinones form stable five-coordinate complexes on reaction with hydrotris(3,5-phenylmethylpyrazolyl)borate zinc hydroxide. Modeling studies suggest that hydroxypyridinonate ligands should be able to access the active site in the enzyme with ease (110). 

Figure 4. Therapeutic strategies to counteract CBP loss of function. CBP loss of function leads to a decrease in histone acetylation levels as well as a decrease in CBP-dependent transcription. Two main approaches can be tested to reverse diis process either resetting HAT functionality or resetting global acetylation levels widi die use of HDAC inhibitors. Whereas both strategies would increase histone acetylation levels, HDAC inhibition would act on a broad range of genes, while CBP activation (overexpression or by a pharmacological approach) would specifically target bodi CBP-dependent histone acetylation and transcription. The structure of some of the HDACi that have been tested in different models, such as small fatty acids and hydroxamic acids, are represented in the boxes...

On the basis of work on enzyme models of low molecular weight, Kunitake and his associates have prepared a variety of vinyl polymers containing the hydroxamate group. Gruhn and Bender (28, 30) investigated compound... 

Hydroxamic acids have been extensively investigated at Abbott, where a hypothetical binding site hypothesis was based on examination of many simple Gj-aralkylhydroxamic acids [294]. Several series of conjugated hydroxamic acids were explored based on this hypothesis, yielding potent 5-LO inhibitors (0.02-2 //M) exemplified by (116)-(119). The most potent of these (119) also inhibited purified porcine leukocyte 5-LO (0.5 //M) [202]. As other workers have found, A-methylation was beneficial for potency. Activity was also seen in a rat peritoneal anaphylaxis model following i.p. (0.2 mg/kg), but not oral, dosing [47]. 

A multiple-path mechanism has been elaborated for dissociation of the mono- and binuclear tris(hydroxamato)-iron(III) complexes with dihydroxamate ligands in aqueous solution. " Iron removal by edta from mono-, bi-, and trinuclear complexes with model desferrioxamine-related siderophores containing one, two, or three tris-hydroxamate units generally follows first-order kinetics though biphasic kinetics were reported for iron removal from one of the binuclear complexes. The kinetic results were interpreted in terms of discrete intrastrand ferrioxamine-type structures for the di-iron and tri-iron complexes of (288). " Reactivities for dissociation, by dissociative activation mechanisms, of a selection of bidentate and hexadentate hydroxamates have been compared with those of oxinates and salicylates. ... 

The published QSAR [59-61] and 3D-QSAR [62-65] models for HDAC inhibitors were used to explain the differences in activity of hydroxamate-based compounds. All the reported models, which showed moderate to good internal predictivity, were mainly used in a retrospectively way to explain the biological activities of H DAC inhibitors. Generally, the 3D-QSAR models were compared with ligand docking results to get insight into the structural requirements for anti-HDAC activity. 

Figure 3.3 Interaction mode of the phenylalanine-containing hydroxamate HDAC inhibitor 5a [53] at HDAC6. The binding mode was derived by docking the inhibitor into a H DAC6 homology model.

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