Phenyl Hydroxamic Acids

Turning attention to the phenyl hydroxamic acids, these are a relatively sparsely explored series of HDACi, probably due to the fact that simple analogs are somewhat less potent HDACis compared to alkyl or cinnamyl linkers. Nevertheless, the group at Celera Genomics was able to identify the phenyl hydroxamic acid 27a, 

The group at Pharmacyclics developed a related phenyl hydroxamic add HDACi, PCI-34051 (27e) and demonstrated this to display greater than 200-fold selectivity for HDAC8 (IC5o = 10nM) over the other HDAC isoforms [40b]. Interestingly, this compound induced caspase-dependent apoptosis in T-cell lymphomas and leukemias at low micromolar concentrations, but not in other hematopoietic or solid tumor cell lines. Furthermore, PCI-34051 does not cause detectable tubulin or histone acetylation. 

HDAC 1 HDAC 2 HDAC 3 HDAC 6 HDACS HDAC 10 

A related N-hydroxybenzylamide that has advanced into phase II clinical studies is ITF2357 (28), developed by Italfarmaco [41]. This compound vas demonstrated to inhibit class I and II HDACs, and to inhibit the proliferation of 9 MM and 7 AML cell lines, with mean ICso s = 0.17 J-M and 0.23 pM respectively. In a mouse model of AML, injected cells home in on the blood, spleen, bone marrow and liver, usually resulting in death in 35-40 days. Daily administration of ITF2357 at 10 or 100 mg/kg resulted in an increase of survival of 6 and 10 days respectively. 

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Hydroxylamine, O-acetyl-A -benzoyl-.V-phenyl-hydroxamic acids from, 2, 506... 

Figure 9.7 SAR exploration of phenyl hydroxamic acid HDACis.

Hydroxylamine, O-acetyl-N-benzoyl-N-phenyl-hydroxamic acids from, 506 Hydroxylamine ligands, 101 Hydrozirconation, 342 Hypoxanthines metal complexes, 93... 

The bis-phosphonium salt (158) promotes the Lessen rearrangement of phenyl-hydroxamic acids and also brings about the Beckmann rearrangement of ketoximes under mild conditions. The salt (159), (formed from the reaction of 2-hydroxyethyl-triphenylphosphonium chloride with phosgene) has been employed as an amino-... 

Molecular modeling was used to design the ligand isophthal-di-A -(4-methyl-phenyl)hydroxamic acid 73 (H2L ). The reaction of 73 with [Ga(acac)3] led to the white microcrystalline precipitate of [Ga4L (j] 74 (Scheme 10) whereas the dark red complex [Fe4L g] was formed in a similar reaction with [Fe(acac)3] [91]. The... 

Alternatively, the oxidation may occur by coupling to a suitable reactant. In 1997, Miyashita explored the scope of oxidative aroylations with nitrobenzene (Scheme ll.lO)." With the same oxidative reagent, nitrobenzene, benzoin reactions had already been developed back in 1982 using cyanide or thiamine. The combination of an aldehyde and nitrosobenzene, in the presence of an NHC, led to the formation of 7V-phenyl hydroxamic acids in good yields. These can be further converted into hydroxamic esters via a one pot reaction in the presence of a second (o,p-unsaturated) aldehyde. Furthermore, the oxidative coupling of aldehydes with carbodiimides in air allowed access to Af-acyl urea derivatives with IMes HCl 19 as the NHC precursor. Related thioesterifications reactions have also been reported using... 

A mixture of 3-hydroxy-4-phenylfurazan and 1,2,4-oxadiazole 243 was prepared from a-phenyl-a-hydroximino hydroxamic acid by acylation and subsequent treatment with 15% aqueous NaOH (Scheme 164) (25G201). The reaction of tetraacetate 244 with sodium acetate hydrate in glacial acetic acid at 70°C gives 3,4-dihydroxyfurazan (9%) (92URP1752734). a-Hydroximino ester 245 reacts with hydroxylamine to form furazan 246 in 25% yield (Scheme 164) (79JHC689). 

The first synthesis of a 3,5-diarylisoxazole from aryl hydroxamic acid chlorides and sodium phenyl acetylides was that effected by Weygand and Bauer in 1927. Beginning in 1946, when Quilico and Speroni showed that acid chlorides of hydroxamic acids on treatment with alkalies readily yielded nitrile oxides,numerous isoxazole and especially A -isoxazoline derivatives have been prepared. 

Figure 6-11. 1 -H-Benzotriazole, 2,5-bis(N-pyridyl)-1,3,4-oxadiazole, cyclohexylammonium benzoate, benzylsulfonylacetic acid, 2,4-diamino-6-mercapto pyrimidine, hydroxamic acid, 3-phenyl-2-propyn-1-ol, dicyclopentadiene dicarboxylic acid.

Deacylation of hydrophobic p-nitrophenyl alkanoates Hydroxamic acid and phenyl ester derivatives had alkyl or fluoroalkyl substituents. Rate effects depend on selectivity of binding of fluoro- and hydro-carbon derivatives Kunitake et ai, 1984... 

FIGURE 7.7 Transacetylation of A-hydroxy-4-acetylaminobiphenyl which converts it from a hydroxamic acid to the more reactive /V-acctoxy-4-arn i nobi phenyl. 

As already mentioned, the field of hydroxamic acid HDACis is extensive, therefore the next paragraphs are divided into sections depending on the nature of the group attached to the hydroxamic acid, including aliphatic, cinnamic, phenyl and heterocyclic hydroxamic acids. 

Researchers at Merck developed a series of benzothiophen-2-yl hydroxamic acids as HDACis [44] tvhich can be considered a hybrid of the cinnamyl and thiophenyl hydroxamic acids. Starting from simple acetyl hydroxamic acid (33a IC50 = 625 pM), they shotved that incremental boost in activity could be achieved introducing first a phenyl ring (IC50 = 20 pM), then replacing this tvith a thiophene (IC50 = 6.6 pM). 

A different approach to A-arylation of hydroxamic acid involves reaction with aromatic iodonium salt , but this reaction has been used for A-phenylation only. 

The general approach to 0-arylation of hydroxylamines involves N-protection followed by O-arylation. Activated aryl halides and heteroaryl halides easily alkylate oxime salts (equation 25), N-aUcyl hydroxamic acids and N-hydroxysuccinimide . N-Hydroxyph-thalimide can be also 0-phenylated through a reaction with diphenyliodonium salt, although in lower yield . ... 

The preparation of A-phenyl-substituted hydroxamic acids 125 in the reaction of formaldehyde with nitrosobenzene to give 124 is strongly catalyzed by Fe + ions, which stabilize the transition states 126 and 127 for the rate-controlling proton transfer from the carbon atom of nitrosocarbinolic cation intermediate 125 leading to the product 128 (Scheme 62) . 

Papot and colleagues have reported the first efficient O-glycosylation of hydroxamic acids 246 (Scheme 110). This process involves the use of glycosyl A-phenyl trifiuoroace-timidates 244 as glycosyl donors to acids 245 in the presence of TMSOTf and 4 A molecular sieves in dichloromethane. 

C13H11NO3 A -Phenyl-2-furanacrylo-hydroxamic acid Bctiaction-photometiic Ti 3... 

C15H13JNU4 iV-Phenyl-2-acetatosalicylo-hydroxamic acid Photomettic Nb, Ti 3... 

C17H15WO2 A-Phenyl-3-styrylacrylo-hydroxamic acid Exttaction-photomett ic Amperometric V Sc 3... 

The chemistry of 1,4-(oxa/thia)-2-azoles, was founded in the late 1930s, when Musante first correctly suggested the 5-imino-2-phenyl 1,4,2-oxathiazole structure (1) for the product obtained from the reaction of ammonium thiocyanate and benzhydroximoyl chloride <38G33l>. Later, Beck described the preparation of dioxazolones (2) and some of their properties <51CB688>, while the first nonconjugated dioxazole derivative (3) was prepared by Exner from hydroxamic acid and benzophenone diethylacetal <56CLY779>. 

Of the many hydroxamic acids R1CONR22(OH) (cf. Section 10.2.5) which give five-membered chelate rings, that with R1 = thienyl and R2 = phenyl or p-tolyl are reported to be highly selective extractants for vanadium(V).52 56 The literature up to 1966 has been reviewed by A. D. Shendri-kar.57... 

The hydrolysis of esters (and amides) by chymotrypsin satisfies these criteria. The hydrolysis of, say, acetyl-L-tryptophan p-i itrophenyl ester forms an acylen-/yme that reacts with various amines such as hydroxylamine, alaninamide, hydrazine, etc., and also with alcohols such as methanol, to give the hydroxamic acid, dipeptide, hydrazide, and methyl ester, respectively, of acetyl-L-tryptophan. The same acylenzyme is generated in the hydrolysis of the phenyl, methyl, ethyl, etc., esters of the amino acid (and also during the hydrolysis of amides). 

Hydrosulfido complexes, 517 bonding, 519 reactivity, 519 structures, 519 synthesis, 518 types, 518 Hydroxamates metal complexes, 505-508 Hydroxamic acid, N-methyl-metal complexes, 507 Hydroxamic acid, phenyl-metal complexes stability, 506 Hydroxamic acids... 

H)-Oxazolones are formed by the spontaneous cyclization of /3-oxo isocyanates (equation 134). Similarly, o-hydroxyphenyl isocyanate, produced by the Curtius rearrangement of the azide of salicylic acid or by the action of sodium hypochlorite on salicylamide, forms benzoxazolone (equation 135). An analogous reaction is the formation of IV-phenyl-benzoxazolone by the action of thionyl chloride on the hydroxamic acid shown in equation (136) (78TL2325). Pyrolysis of aryl azidoformates affords benzoxazolones by nitrene insertion (equation 137) (81CC241). 

The nitrone of piperidine reacts with phenyl vinyl ether to yield a 1,3-dipolar cycloaddition product. Benzylation led to a ring-opened product which was converted to a hydroxamic acid. This is desired functionality in medicinal chemistry because it is a metal-binding ligand <03S1221>. 

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