Hydroxamic acids acid sites

Medium Method Hydroxamic acid Acid site Reference... 

The second group of hydroxamate-based chelators consists of biomimetic ferrichrome analogs modified by introducing hydrophobic amino acids between the template and the hydroxamic acid binding sites 59, 60, 66, 68, 70, 199 and 200. Since they function to withhold iron from cells in contrast to their original function of iron delivery, they were named reversed siderophores (RSF) . ... 

Zn -PDF, 37 pM versus E. coli Fe -PDF), it was successfully used to provide co-crystals bound in the active site of both Co - and Zn -E. coli PDF [58], These structures reveal that the H-phosphonate binds to the metal in a monodentate fashion, adopting a tetrahedral coordination state similar to that of the native resting state of the enzyme. This is in contrast to later co-crystal structures obtained with more potent hydroxamic acid or reverse hydroxamate inhibitors, which bind to the metal in a bidentate fashion vide infra). Presumably these bidentate inhibitors mimic the true transition state of the enzyme, in which the metal centre slips to a penta-coordinate geometry in order to activate the Wformyl carbonyl of the substrate [56, 67]. 

JMJD2 demethylases are inhibited by analogues of the cofactor 2-OG that include N-oxalylamino acids, pyridine dicarboxylates, and related bipyridyl derivatives. Other chemotypes that are also presumed to bind to the active-site Fe(II) include catechols, hydroxamic acids (including the clinically used HD AC inhibitor SAHA/Vorinostat), and tricarboxylic acid cycle intermediates, such as succinate and fumarate [59,62]. 

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). 

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]. 

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]. 

Figure 9.1 (a) Representation of crucial binding interactions of hydroxamic acid inhibitor in the HDAC active site (HDAC8 numbering), (b) Proposed catalytic mechanism. 

Before ending this chapter, we would like to draw attention to another type of electrostatic intermolecular interaction that could be quite relevant to hydroxylamines, oximes and hydroxamic acids. We refer to a-hole bonding. This is a highly-directional, nonco-valent interaction between a region of positive electrostatic potential (or cr-hole) on an outer portion of a Group V, VI or VII covalently-bonded atom and a negative site on... 

There has been considerable interest in the last two decades in the site of acidity of hydroxamic acids. There are two possible acidity sites the NH and OH fragments in the C(0)NH0H group. It was originally assumed that these compounds were acidic due to the OH group. Since then, much effort has been expended on the determination of the site of proton transfer under various conditions by both experimental and computational studies. The proton transfer leads to the following possible products ... 

TABLE 7. Experimental determination of the acid site in hydroxamic acids... 

TABLE 8. Computational determination of acid site and conformation of hydroxamic adds... 

In XC(0)NHOH for NH acidity n = 2, for OH acidity n = 3. Clearly, best agreement is with n = 3. This suggests that in water, hydroxamic acids are oxygen acids. Also examined were the XCH2C(0)NHOH (set HA13) for which the n values of the NH and OH sites are 3 and 4, respectively. Correlation of the pXa values for these acids with the LDR equation gave the regression equation 56 ... 

The degeneracy of the non-chiral complexes can be removed by incorporating chiral centers, usually as resolved amino acids, into the arms at close vicinity to the hydroxamate iron binding sites. Thus, only one of the energetically non-equivalent diastereomers predominates, leading to pure enantiomeric iron(III) complexes with defined hehcity that allows assessing stereospecific recognition by the ferrichrome receptor. 

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