Hydroxamate structure

Siderophores with citrate-hydroxamate structures (schizokinen, arthrobactin and aerobactin) are synthesized by enteric bacilli and Arthrobacter spp. Their structures are shown in Figure 48. 

No simple pteridine 1- or 3-oxides are yet known. If the AT-atom of an amide function is formally oxidized, tautomerism favours the cyclic hydroxamic acid structure, as found for 3-hydroxypteridin-4-one (55JA3927), 1-hydroxylumazine (64JOC408) and 2,4-diamino-8-hydroxypteridin-7-ones (75JOC2332). 

The following discussion of hydroxamic acids includes saturated systems, e.g., 2, compounds such as 3, derived from aromatic systems, 7V-hydroxyimides such as 7V-hydroxyglutarimide (78), and certain of their derivatives including thiohydroxamic acids. Naturally occurring cyclic hydroxamic acids are discussed to show the range of structural types that has been found, hut macrocyclic polyhydroxamic acids are mentioned very briefly, because several comprehensive reviews of these compounds are already available. The main purpose of this review is to summarize the methods available for the synthesis of cyclic hydroxamic acids, to outline their characteristic reactions, and to present some useful physical data. Their synthesis and some biological properties have previously been reviewed by Coutts. ... 

For the present purpose this is not a useful scheme and the naturally occurring compounds are arranged instead in order of increasing molecular complexity. Compounds that do not contain a cyclic hydroxamic acid structure are excluded. 

Because of the great range of structures containing cyclic hydroxamic acid functions it is difficult to give a concise summary of the available synthetic methods. Nevertheless, the vast majority of published syntheses depend on condensation reactions involving only familiar processes of acylation or alkylation of hydroxylamine derivatives. The principles of such syntheses are outlined in a number of typical examples in Section III, A but no attempt has been made to cover all reported cases. 

In one particular example, an interesting intramolecular acylation occurred. Reduction of cis-iVi-acetyl-o-nitrobenzylideneoxindole (55) gave rise to a cyclic hydroxamic acid, assigned structure 56. 

On the basis of such eliminations and the acid strengths of the corresponding unsaturated hydroxamic acids, Kochetkov et concluded that the structures of 53a and 53b are opposite to those shown. 

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]. 

British Biotech has described co-crystal structures of both BB-3497 and actinonin bound in the active site of E. coli PDF [24]. The metal centre (Ni ) in both complexes adopts a pentacoordinate geometry, bound by the two oxygen atoms of the hydroxamate along with Cys-90, His-132 and His-136. This coordination pattern is consistent with the mechanism of de-formylation proposed by Becker et al. [56] and Jain et al. [67], in which a pentacoordinated metal centre stabilises the transition state during hydrolysis of the formamide bond. When compared to the co-crystal structure of a substrate hydrolysis product, Met-Ala-Ser, it is clear that the side chains of these two inhibitors bind into the active site pockets similarly to the substrate [56]. 

Researchers at Novartis, Senju and Hoffman-La Roche have reported structurally related bicyclic hydroxamic acids as potent PDF inhibitors [106-108]. In 2001, screening efforts at Hoffman-LaRoche identified hydrazide (28)... 

Schering Plough has reported the discovery of the first non-hydroxamic acid containing natural product inhibitors of PDF. Sch 382582 (41) and Sch 382583 (42) were isolated from a fermentation broth of Streptomyces sp., and the proposed structures of these compoimds were derived from a combination of two-dimensional NMR studies (NOESY, HMBC and HMQC-TOCSY) and X-ray crystallography studies [116]. The proposed structure... 

Moy FJ, Chanda PK, Chen JM, Cosmi S, Edris W, Skotnicki JS, Wilhelm J, Powers P. NMR solution structure of the catalytic fragment of human fibroblast collagenase complexed with a sulfonamide derivative of a hydroxamic acid compound. Biochemistry 1999 38 7085-7096. 

Another factor that relates complex stability and siderophore architecture is the chelate effect. The chelate effect is represented by an increase in complex stability for a multidentate ligand when compared to complexes with homologous donor atoms of lower denticity. The effect can be observed when comparing the stability of complexes of mono-hydroxamate ligands to their tris-hydroxamate analogs, such as ferrichrome (6) or desferrioxamine B (4). However, the increase in stability alone is not sufficient to explain the preponderance of hexadentate siderophores over tetradentate or bidentate siderophores in nature, and the chelate effect is not observed to a great extent in some siderophore structures (10,22,50,51). 

In addition to structure, the dihydroxamate connecting chain length will affect the affinity of linear siderophores and side-rophore mimics for iron(III) (Table IIIA). If the chain connecting the hydroxamates is long, there will be a significant entropic... 

The presence in the heterocycle of additional basic centers or those open to alkylation can lead to a change in reaction directions. It essentially limits the application of this method in the formation of a-methoxy nitrones. In such cases, it is reasonable to use diazomethane and, depending on the structure of hydroxamic acid (198-201) the yields of a-methoxy nitrones (197), (202-204) can rise from 17% up to 62% (Scheme 2.70) (353). 

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