Inhibitors hydroxamates

INHIBITORS OF MAMMALIAN COLLAGENASES Non-substrate analogue inhibitors Substrate analogue inhibitors Phosphorus-based inhibitors Sulphur-based inhibitors Hydroxamate inhibitors tt-Carboxyalkyl inhibitors Miscellaneous inhibitors... 

Keywords Histone deacetylase HDAC inhibitor Hydroxamic acid ... 

D. W. Fong and B. S. Shambatta. Hydroxamic acid containing polymers used as corrosion inhibitors. Patent CA 2074535,1993. 

Payne, A.N., Jackson, W.P., Salmon, J.A., Nicholls, A., Yeadon, M. and Garland, L.G. (1991). Hydroxamic acids and hydroxyureas as novel, selective 5-lipoxygenase inhibitors for possible use in asthma. Agents Actions 34, 189-199. 

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]. 

Additional P2 proline-containing PDF inhibitors have been reported in the patent literature by Dainippon and Questcor [95, 96]. The Dainippon examples disclosed contain an A-formyl-A-hydroxylamine group and possess good antibacterial activity against S. aureus, S. pneumoniae, Streptococcus pyogenes. Enterococcus faecium and M. catarrhalis [95]. The Questcor patent application describes various proline-containing hydroxamic acid inhibitors [96]. 

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)... 

More recently, screening efforts at Novartis have identified a hydroxamic acid containing a benzothiazinone ring system (32) [108]. This inhibitor is very potent versus S. aureus Ni -PDF (<5nM) and displays good selectivity versus matrix metalloprotease-2 (MMP-2) and MMP-13. Unfortunately (32), and all other analogues prepared, such as carbon isosteres (33), sulfones (34), N-substituted analogues (35) and N-formyl-N-hydroxylamines (36), lacked appreciable antibacterial activity in spite of their potent enzyme inhibitory activity. Further studies performed by Novartis suggest that these molecules are unable to penetrate the outer cell membrane of E. coli, and may bind to the cell membrane of S. aureus [108]. 

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. 

In the patent literature, Aventis has published a patent application covering hydroxamic acid containing macrocycles (39) with the same general template as the A-formyl-A-hydroxylamine macrocycles described above [114] and GlaxoSmithKline has published an application on macrocyclic PDF inhibitors containing a hydrazide scaffold (40) [115], No data has been published on these inhibitors to date. 

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... 

Kelly WK, Marks PA (2005) Drug insight histone deacetylase inhibitors - development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol 2 150-157... 

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]. 

An alternative procedure for the synthesis of aliphatic 2-substituted oxazoline hydroxamates was described by Pirrung and colleagues in the context of preparing inhibitors of E. coli LpxC zinc amidase [378], As shown in Scheme 6.210 a, the protocol involved the cyclization of suitable amides, formed in situ by acylation of a serine-derived 0-2,4-dimethoxybenzyl (DMB)-protected hydroxamate. The cyclization... 

More recently, an additional approach to preventing TNF toxicity has been proposed. Several metalloprotease inhibitors (most notably hydroxamic acid) prevent proteolytic processing (i.e. release) of TNF-a from producer cell surfaces. Such inhibitors may also prove useful in preventing TNF-induced illness. The extent to which TNF (and inhibitors of TNF) will serve as future therapeutic agents remains to be determined by future clinical trials. 

Isoxazole-3-hydroxamic Acid Derivatives as Potential PDF Inhibitors. . . 193... 

Synthesis of a Carbohydrate-Derived Hydroxamic Acid Inhibitor of LpxC. 200... 

AT-Alkyl Urea Hydroxamic Acids as PDF Inhibitors with Antibacterial Activity... 

Based on the proposed generic PDF inhibitor structure and by incorporating the hydroxamic acid moiety, Hackbarth et al. [77] and Lewis et al. [78]... 

Scheme 22 Synthesis of N-alkyl urea hydroxamic acids as PDF inhibitors...

The idea for macrocydic peptidomimetic inhibitors of PDF originated from the structure of the reverse hydroxamate BB-3497 that was reported by Clements et al. [73]. On this basis, Hu et al. [81] designed the cyclic compound 135, in which a nonyl group serves as the cross-linked Pi and P3 side chain, as depicted in Fig. 8. 

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