Heterocycle Hydroxamic Acids

Number Spacer Ar HDAC1 MCF7 Number Ar HDAC1 MCF7 

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). 

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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. 

Figure 9.8 SAR exploration of heterocyclic hydroxamic acid HDACis.

The tenth volume of this serial publication comprises six chapters, four of which deal with the general chemistry of a specific group of heterocyclic compounds pyridopyrimidines (W. J. Irwin and D. G. VVibberley), benzofuroxans (A. J. Boulton and P. B. Ghosh), isoindoles (J. D. White and M. E. Mann), and pyrylium salts (A. T. Balaban, W. Schroth, and G. Fischer). The remaining chapters are concerned with indole Grignard reagents (R. A. Heacock and S. Kasparek) and with cyclic hydroxamic acids (J. B. Bapat, D. St. C. Black, and R. C. Brown).The international flavor of the publication is preserved our contributors come from six countries in three continents. 

A seemingly complex heterocycle which on close examination is in fact a latentiated derivative of a salicylic acid shows antiinflammatory activity. It might be speculated that this compound could quite easily undergo metabolic transformation to a salicylate and that this product is in fact the active drug. Condensation of acid 134 with hydroxyl amine leads to the hydroxamic acid 135. Reaction of... 

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). 

Benzamides e.g. MS-275 8 are one of the more common hydroxamic acid alternatives but are often less potent. Recent exceptions to this pattern include substituted pyridyl [29] and thiazolyl [30] benzamides, such as 9 and 10 with HDAC1 enzyme IC50s of 19nM and 29 nM, respectively and series of benzamides substituted with other heterocycles, such as indazoles [31] and benzo [l,2,4]thiadiazines [32], many with HDAC2 IC50s of <50 nM. The addition of... 

The enzyme can also catalyze the transfer of an acetyl group from an N-acetylated hydroxylamine (hydroxamic acid) to form an acetoxy product, i.e., an N to O transacetylation and this pathway does not require acetyl Co-A (12). A-hydroxy-4-acetylaminobiphenyl provides an example of this conversion as shown in Figure 7.7. The significance of this pathway is that it leads to the activation of the hydroxamic acid because acetoxy derivatives of aromatic amines are chemically reactive and many are carcinogens such as the heterocyclic amines formed when meat is heated to a high temperature, e.g., 2-amino-1-mcthyl-6-phenylirnidaz()[4,5-i ]pyri(linc. 

From the same laboratories, a series of heterocyclic ketones were published as HDAC inhibitors [61]. This work is a continuation and further elaboration of the concept of the use of electrophihc ketones as hydroxamic acid replacements. a-Keto oxazole derivatives appeared to act as the most potent HDAC inhibitors in the HDAC1/HDAC2 enzyme assay [60], displaying low micromolar activity (Fig. 9). 

Scheme 2 demonstrates that [3,3] rearrangements of hydroxylamines, oximes or hydroxamic acids are a versatile synthetic tool to prepare different heterocyclic rings such as indoles, imidazoles, benzofurans and oxazolidines which are useful synthetic precursors of natural products. 

The first term of the rate law requires acid-catalyzed decomposition of the conjugated acid of the ester. This term predominates only under strongly acidic conditions. It has not been investigated in detail, but the major product of the acid catalyzed reaction is the corresponding hydroxylamine. The second term predominates under neutral to mildly acidic conditions. This term is consistent with uncatalyzed heterolysis of the N—O bond of the neutral ester to generate a heteroaryinitrenium ion. " The rate law is more complicated than that for reactive esters of carbocyclic hydroxylamines or hydroxamic acids that show pH-independent decomposition over a wide pH range. The kinetic behavior of the heterocyclic esters is caused by protonation of a pyridyl or imidazolyl N under mildly acidic conditions. The protonated substrates are not subject to spontaneous uncatalyzed decomposition, so decreases under acidic conditions until acid-catalyzed... 

Homolytic substitution of heteroaromatic compounds, 16, 123 Hydantoins, chemistry of, 38, 177 Hydrogen cyanide derivatives, synthesis of heterocycles from, 41, 1 Hydrogen exchange base-catalyzed, 16, 1 one-step (labeling) methods, 15, 137 Hydrogenated porphyrin derivatives hydroporphyrins, 43, 73 Hydroxamic acids, cyclic, 10, 199 1 -Hydroxyindoles, 1 -hydroxytryptophans, and 1-hydroxytryptamines,... 

Diels-Alder precursor hydroxamic acid 174 (prepared by a multistep reaction) was subjected to subsequent oxidation and cycloaddition to provide bicyclic intermediates 175, which underwent ring cleavage by reduction with Na(Hg) amalgam, affording the eight-membered heterocycle 176 (Scheme 74 <2004JOC3025>). 

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