Hydroxamate residues

The ferrioxamines form a large group of ferric trihydroxamates composed of residues of acetic acid, succinic acid, l-amino-5-hydroxyl-aminopentane, and l-amino-4-hydroxylaminobutane. Of the.se, only ferrioxamines E (14) and D2 (15) are formally cyclic hydroxamic acids. 

Koster, W. and Bohm, B. (1992). Point mutations in 2 conserved glycine residues within the integral membrane protein FhuB affect iron (III) hydroxamate transport, Mol. Gen. Genet., 232, 399-407. 

Although the simple hydroxamate analogues of arachidonic acid showed no anti-inflammatory activity, the concept prompted a number of research groups to explore hydroxamic acids with more stable lipophilic residues. This approach has yielded some of the most interesting anti-inflammatory 5-LO inhibitors reported to date. 

A number of other scissile bond replacements have been explored in an attempt to produce inhibitors of the bacterial collagenases, but all have exhibited relatively low potency Table 8.6). These include a compound with an A-methylamide residue in subsite P l (46), two carboxylates (47)-(48), the hydroxamate N-terminal (49) and C-terminal analogues (50)-(51), and one A-carboxyalkyl (52) derivative. 

The hydroxamate functionality is an effective scissile bond surrogate in collagenase inhibitors [1,186-203], probably because of its ability to serve as a bidentate ligand for the active site Zn(II). N-terminal tri- and tetrapeptide hydroxamate substrate analogues are only moderately potent inhibitors Table 8.15). An intriguing observation with respect to possible binding modes is that the residues in subsites P and P2 can be replaced with their D-stereoisomer counterparts with essentially no loss of potency, as long as both are replaced with the D-isomers (compare (151), (152) and (153), and (154) vs. (157), in Table 8.15). 

Fig. 5. Acyl residues encountered in fungal hydroxamate siderophores...

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]. 

Hydroxamic acids of general structure R—CO—NH—OH, having R as an organic residue, have been known since 1869 with the discovery of oxalohydroxamic acid by Lossen . Despite this, researches on these compounds were lacking until the 1980s, after which an enormous amount of information has accumulated with respect to their biomedical applications, synthesis, and the determination of the structures of their metal complexes. ... 

Limited carbonyl NMR data are available for these anomeric amides. However, carbonyl shifts for hydrazines 217 and 218 were on average 3 ppm higher than their hydroxamic ester precursors. This reflects a higher degree of residual amide resonance in the hydrazines relative to A-acyloxy-iV-alkoxyamides where the difference was closer to 8.0 ppm. As reported for A-acyloxy-A-alkoxyamides (see Section IV.B.2), analysis of variance in the hydrazine and hydroxamic ester shifts indicates that substituents affect the hydroxamic ester carbonyl shifts ( 2.6) more than those of the hydrazines ( 1.3 ppm). 

The teichoic acid shows an infrared absorption band at 1751 cm.-1, characteristic of carboxylic ester groups, which is not observed in samples from which the D-alanine residues have been removed. Removal of the u-alanine was readily effected with ammonia or hydroxylamine, when D-alaninamide or D-alanine hydroxamate were formed. The kinetics of the reaction with hydroxylamine reveal the high reactivity of its D-alanine ester linkages, which, like those in most other teichoic acids, are activated by the presence of a neighboring phosphate group. That the D-alanine residue is attached directly to the ribitol residues, instead of to the d-glucosyl substituents, was also shown by oxidation with periodate under controlled conditions of pH, when it was found that the D-alanine residues protect the ribitol residues from oxidation. Under the same conditions, all of the ribitol residues were oxidized in a sample of teichoic acid from which the D-alanine had been removed, and it is concluded that the ester groups are attached to C-2 or C-3 of the ribitol residues. 

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