Non-hydroxamates

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... 

In a simultaneous attempt to screen for further non-hydroxamate ZBGs, this team focussed on potentially bidentate ZBGs and identified a SAHA-like compound with a mercaptoacetamide functionality, which had an HDAC enzyme... 

Suzuki, T., Nagano, Y, Kouketsu, A., Matsuura, A., Maruyama, S., Kurotaki, M. et al. (2005) Novel Inhibitors of human histone deacetylases design, synthesis, enzyme inhibition, and cancer cell growth inhibition of SAHA-based non-hydroxamates. Journal of Medicinal Chemistry, 48, 1019—1032. 

Hurwitz H, Humphrey J, Williams K, Ness E, Conway A, Bielefield M, et al. A phase I trial of BMS-275291 a novel, non-hydroxamate, sheddase-sparing matrix metalloproteinase inhibitor (MMPI) with no dose-limiting arthritis. Proc Anna Meet Am Soc Clin Oncol 2001 (abstract) submitted. 

Chiu T, Solberg J, Patil S et al (2009) Identification of novel non-hydroxamate anthrax toxin lethal factor inhibitors by topo-meric searching, docking and scoring, and in vitro screening. J Chem Inf Model 49 2726-2734... 

Sheppeck JE, Gilmore JL, Yang A et al (2007) Discovery of novel hydantoins as selcective non-hydroxamate inhibitors of tumor necrosis factor-a converting enzyme (TACE). Bioorg Med Chem Lett 17 1413-1417... 

Sheppeck, J. E., II, Gilmore, J. L., Tebben, A., et al. (2007) Hydantoins, triazolones, and imid-azolones as selective non-hydroxamate inhibitors of tumor necrosis factor-oc converting enzyme (TACE). Bioorganic Medicinal Chemistry Letters, 17, 2769-2774. 

Pseudopeptidic Hydroxamic Acids and N-formyl-N-hydroxylamines Non-peptidic Templates... 

Iron transport agents may belong to the protein or non-protein class. In the former group are found the animal proteins transferrin (25), lactoferrin (26) and conalbumin (27). The low molecular weight iron carrying compounds from microorganisms, the siderochromes, may occur with or without a bound metal ion. Typically, severe repression of biosynthesis of these substances can be expected to set in at an iron concentration of ca. 2 x 10-5 g atoms/liter (28). Most, but not all, of these substances can be described as phenolates or hydroxamates (4). 

Fe(III) displacement of Al(III), Ga(III), or In(III) from their respective complexes with these tripodal ligands, have been determined. The M(III)-by-Fe(III) displacement processes are controlled by the ease of dissociation of Al(III), Ga(III), or In(III) Fe(III) may in turn be displaced from these complexes by edta (removal from the two non-equivalent sites gives rise to an appropriate kinetic pattern) (343). Kinetics and mechanism of a catalytic chloride ion effect on the dissociation of model siderophore-hydroxamate iron(III) complexes chloride and, to lesser extents, bromide and nitrate, catalyze ligand dissociation through transient coordination of the added anion to the iron (344). A catechol derivative of desferrioxamine has been found to remove iron from transferrin about 100 times faster than desferrioxamine itself it forms a significantly more stable product with Fe3+ (345). 

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

Intramolecular addition of hydroxylamines and hydroxamic acids to the non-activated double bonds is possible through oxidative cyclization. Reaction of O-Acyl fi,y-unsaturated hydroxamates (e.g. 56, equation 38) with bromine provides 3,4-substituted iV-hydroxy -lactams such as 57 with high diastereoselectivity. Analogous reaction of O-benzyl hydroxylamine 58 (equation 39) with iodine results in five-membered cyclization with 2 1 ratio of diastereomers. ... 

Dioxazoles 146 are readily prepared by transketalization of 2,2-diethoxypropane, where both the NH and OH moieties are protected in a non-protic form (Scheme 68). The dioxazoles 146 are stable to a wide variety of reaction conditions and readily revert back to the hydroxamic acids 145 and isopropyl ester 147 (145/147 50/1) by treatment with Nafion-H in 2-propanol. The method is applicable to primary, secondary, tertiary and aromatic hydroxamic acids, and the acidity of the protons adjacent to the dioxazole allows R-functionalization. 

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. 

Among the many other non-oxicam-type substances discovered are a sultam pro-drug for potential P3-lactam thrombin inhibitors <1998BML3683>. Furthermore, an anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) pharmacophore based on the 1,2-thiazine structure has also been recently disclosed <1999BML673>. Workers at Bristol-Meyers Squibb have synthesized and evaluated sultam hydroxamates as MMP-2 inhibitors <2004JME2981>. Hydroxamate 38 displayed the best selectivity for MMP-2 over the other proteins in this superfamily of peptidases (Figure 27). As noted in Section 8.07.3.1, an X-ray crystal structure of 38 bound to the protein MMP-13 protein has been solved. 

Less than 0.07% of the recovered urinary radioactivity in rats given 100 or 1000 mg/kg bw [ Clacetamide coeluted upon high-performance liquid chromatography with an N-hydroxyacetamide standard and this hydroxamic acid could not be detected after incubation of acetamide with rat liver microsomes and NADPH or in primary cultures of rat hepatocytes. [ C]Acetamide does not bind covalently to proteins in the presence of rat liver microsomes and NADPH or cytosolic fraction, whereas hepatocyte cultures contained non-extractable radioactivity. This association was inhibited by cycloheximide to the same extent as [ CJacetate incorporation into cellular proteins (Dybing et al., 1987). 

The selectivity of the 1,3,5-triazines towards plants is primarily determined by the pathway and the rate of detoxication of these compounds in a given plant. Non-enzymatic hydrolysis of chloro-l,3,5-triazines is catalyzed by cyclic hydroxamates such as 2,4-dihydroxy-7-methoxy-l,4-benzooxazin-3(2//)-one, but the degree of tolerance to the triazines does not coincide with the content of these compounds. The chloro-l,3,5-triazines can be completely... 

Hydroxamic acids have been the subject of six papers 43 90 94 Earlier the operation of the a-effect in the reaction of p-nitrophcnyl acetate with benzohydroxamates in aqueous MeCN was discussed.43 The conformational behaviour of series of mono- (105) and di-hydroxamic acids (106) in MeOH, DMSO, and chloroform and in the solid state has been examined witii IR and NMR spectroscopy.90 X-ray crystal structure determinations of (105 X = Me, R = Me) and die monohydrate of glutarodihydroxamic acid (106 n = 3, R = H) together widi ab initio MO calculations for several hydrated and non-hydrated acids have been performed. The cis-Z conformation of the hydroxamate groups is preferentially stabilized by H-bonding witii water. 

Moxalactam is also amenable to the popular hydroxyl amine assay for g-lactam antibiotics. In this procedure the -lactam is reacted with hydroxyl amine to cleave the e-lactam moiety and form a hydroxamic acid. The hydroxamic acid will in turn react with acidified ferric ion to form a colored complex which is measured at 480 nm. A blank correction for non-e-lactam impurities which react with hydroxyl amine is incorporated by adding hydroxylamine to an acidified sample where the acid is used to destroy all e-lactam species. 

A neutral, ninhydrin-positive, non-extractable (from aqueous media), viscous syrup. Rf in butanol-acetic acid-water, 0.32 (Rf values known in four other solvents). Hydroxamic linkage cleaved in 2 hrs at 50° in 0.5N HC1, yielding N8-hydroxyornithine. Reductive hydrolysis in 48%... 

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