Hydroxamic acid biological activity

Heterosteroids, synthesis, structure, and functions 82MI9 78KFZ(4)22. Heterocyclic derivatives of hydroxamic acid, biological activity of ... 

Mikes and Turkova have given a classification of naturally occurring hydroxamic acids in terms of their biological function or activity. They have distinguished (a) growth factors, e.g., ferri-chromes, mycobactin, and ferrioxamines, ferrichrysins, ferrirubins, etc. (6) antibiotics, e.g, aspergillic acid, mycelianamide, albomycin, nocardamine and (c) microbial pigments such as pulcherrimin. 

The identification of the first small molecule HDAC inhibitors in the late seventies triggered an exponential growth in medicinal chemistry activity. Three decades and many thousand compounds later, the availabiUty of diverse HDAC inhibitors such as short-chain fatty acids, hydroxamic acids, benzamides and tetracyclic peptides, has not only enabled the elucidation of the catalytic mechanism underlying the deacetylating capacity of HDACs, but has also assisted in the investigation of the biological role of the various HDAC subtypes. Furthermore, HDAC inhibitors are currently being evaluated in the clinic and have shown therapeutic potential in the treatment of cancer. 

Biological activity of gramine and hydroxamic acids. Gramine... 

Since differences were often reported in product yields from photochemical and thermal reactions, it was not clear that the same intermediate was generated in both cases. This issue was complicated by the fact that the temperatures under whieh the two experiments were run were usually quite different. The acid-base chemistry of nitrenium ions was largely unexplored so it was not known under what conditions these species could be protonated or deprotonated. It had also not been demonstrated that nitrenium ions played any role in the biological activity of mutagenic and carcinogenic esters of N-arylhydroxylamines or hydroxamic acids, particularly in their reactions with the DNA bases. Over the next decade these issues would be resolved but many questions about nitrenium ion chemistry would remain unanswered. 

The fundamental structural unit of the ferrichromes, N -hydroxyomithine, is also present in rhodotorulic acid (and related compounds), the fusarinines (Ns-acyl-Ns-hydroxyornithine) and in neurosporin. The diversity of structure and biological activity of these siderophores results from the various substituents present in the peptide and acyl groups. The hydroxamate siderophores are better characterized from a structural viewpoint. X-ray diffraction data are available for the... 

Generally, A-oxide metabolites show an antibiotic activity in microorganisms and a convulsive effect in animals. On the other hand, deoxy compounds do not. The hydroxamic acid moiety in these metabolites seems to be essential for exhibition of their biological activities. Usually, deoxy compounds have a fluorescent violet color, whereas A-oxides are not fluorescent (9b). It seems useful to distinguish mycotoxin-producing fungi in seed. 

Oxidation Mechanism of Hydroxamic Acids Forming HNO and NO Implications for Biological Activity... 

Molz et al. synthesized monomers containing the cytostatic bis(2-chloroethyl)amino group linked via urethane or 0-acylated hydroxamic acid bonds to polymerizable methacrylic acid derivatives. Copolymers with hydrophilic monomers, e.g. 2-(methyl-sulfinyl)ethyl methacrylate, yielded biologically active compounds of the structure... 

It has been generally demonstrated that pyrazine 1-oxides are biologically active but that the deoxy derivatives are not. The hydroxamic acid moiety of these compounds is probably a major structural requirement for the exhibition of their biological activity, because the compounds containing the hydroxamic acid moiety show an antibiotic effect on microorganisms and a convulsive effect on animals. The naturally occurring fungal pyrazine 1-oxides are shown in Table II. 

Figure 8.5 PolyP accumulation, and polyphosphate kinase (PPK) and exopolyphosphatase (PPX) activities, under stringent conditions. E. coli MG1655 was grown on a MOPS medium containing 0.4 mM P . At A540 near 0.2, serine hydroxamate (SHX) was added (0.5 mg mO1) for induction of amino acid starvation and accumulation of (p)ppGpp. Symbols represent with ( ) and without (<0>) serine hydroxamate units of PPK and PPX in (b) are 1 nmol P muT1 (Kuroda et al., 1997). Reproduced with permission from Kuroda, A., Murphy, H., Cashel, M. and Kornberg, A., J. Biol. Chem., 272(34), 21240-21243 (1997). Copyright (1997) American Society for Biochemistry and Molecular Biology.

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