Hydroxamic acids, coordination

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]. 

Metal alkoxides undergo alkoxide exchange with alcoholic compounds such as alcohols, hydro-xamic acids, and alkyl hydroperoxides. Alkyl hydroperoxides themselves do not epoxidize olefins. However, hydroperoxides coordinated to a metal ion are activated by coordination of the distal oxygen (O2) and undergo epoxidation (Scheme 1). When the olefin is an allylic alcohol, both hydroperoxide and olefin are coordinated to the metal ion and the epoxidation occurs swiftly in an intramolecular manner.22 Thus, the epoxidation of an allylic alcohol proceeds selectively in the presence of an isolated olefin.23,24 In this metal-mediated epoxidation of allylic alcohols, some alkoxide(s) (—OR) do not participate in the epoxidation. Therefore, if such bystander alkoxide(s) are replaced with optically active ones, the epoxidation is expected to be enantioselective. Indeed, Yamada et al.25 and Sharp less et al.26 independently reported the epoxidation of allylic alcohols using Mo02(acac)2 modified with V-methyl-ephedrine and VO (acac)2 modified with an optically active hydroxamic acid as the catalyst, respectively, albeit with modest enantioselectivity. 

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... 

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). 

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]. 

While coordination chemistry of hydroxamic acids has been studied extensively (particularly with Cu(II), Zn(n), Fe(III), Co(III), and Cr(III) ions) there have been only few reports in the literature on the formation of Cr(V) complexes of these ligands. The current interest in coordination chemistry of Cr(V) arises mainly from the proposed crucial role of reactive Cr(V) intermediates in Cr(VI)-induced genotoxicity and carcinogenicity . ... 

With a twist on the Sharpless asymmetric epoxidation protocol, Yamamoto and co-workers <99JOC338> have developed a chiral hydroxamic acid (17) derived from binaphthol, which serves as a coordinative chiral auxiliary when combined with VO(acac)j or VO(i-PrO)j in the epoxidation of allylic alcohols. In this protocol, triphenylmethyl hydroperoxide (TiOOH) provides markedly increased enantiomeric excess, compared to the more traditional t-butyl hydroperoxide. Thus, the epoxidation of E-2,3-diphenyl-2-propenol (18) with 7.5 mol% VO(i-PiO)3 and 15 mol% of 17 in toluene (-20 °C 24 h) provided the 2S,3S epoxide 19 in 83% ee. 

Hydroxamic acid exists in two tautomeric forms, (1) and (2), and such keto-enol tautomerism provides a number of sites for coordination and chelation. The keto form (1) predominates in acid media and the enol form (2) in alkaline media 25 this has been corroborated by the extraction of vanadium benzohydroxamic acid complexes in organic solvents.26... 

The N-hydroxy amino acid derivatives are likely to be applicable to other metalloproteases. Thermolysin is inhibited irreversibly at pH 7.2 by ClCH2CO-DL-HOLeu-OCH3 where HOLeu is N-hydroxyleucine (47). The inhibition reaction involves coordination of the hydroxamic acid functional group to the active-site zinc atom of the enzyme. This then places the chloroacetyl group adjacent to Glu-143, an essential catalytic residue of thermolysin (see Figure 9). An ester linkage is formed and the enzyme is inactivated irreversibly. This reagent also inactivated two neutral metalloproteases from B. subtilis, but reacted only very slowly with carboxypeptidase A (t1/2 > 3 d). 

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