L-Isoleucine hydroxamic acid

Neoenactins (NEs) are L-serine-containing antifungal antibiotics produced by Streptoverticillium olivoreticuli. The effect of supplementation of individual amino acids on the production of NEs by this organism was examined from both quantitative and qualitative view points by using a nitrogen source-restricted medium. L-Alanine, L-arginine, L-glutamine, L-histidine, L-lysine and L-proline increased significantly the total productivity of NEs without changing the production ratio of the congeners. The supplementation of L-norvaline, L-isoleucine, L-leucine and L-valine to the culture medium resulted in selective enhancement of the production of NEs A, B1, B2, and M1, respectively, while significant change was not observed in terms of overall production of NEs. When L-norleucine was employed as an amino acid supplement, new NE congeners, named NEs NL1 and NL2, were preferentially produced; but the amount of NEs produced was not markedly affected.

Epigenetic targeting of different cancers by inhibiting particular histone deacetylase (HDAC) isozymes is a promising treatment approach against cancer. Development of locally-implantable molecular inhibitors of HDAC (henceforth called HDACi) promises high tumour site concentration and reduced systemic degradation of the HDACi. Herein, we report the design of such implantable HDACi based on amphiphilic derivatives of hydrophobic amino acids endowed with a hydroxamic acid (hxa)-based zinc-binding residue. The amino acids present in HDACi influenced the HDAC isozyme that could be inhibited most effectively; the l-phenylalanine derivative 4e inhibited the HDAC6 isozyme most potently (IC50 ~ 88 nM), while the l-isoleucine derivative 4h was most effective against the isozyme HDAC2 (IC50 ~ 94 nM). We also noticed that the l-Phe derivative 4e was up to 5× more potent towards inhibiting HDAC6 than its optical antipode 4f derived from d-Phe. This was rationalized in terms of the varying extent of penetration of the enantiomeric inhibitors inside the catalytic tunnel of the enzyme. Since the isozymes HDAC6 and HDAC2 are overexpressed in different cancer cells, 4e and 4h elicited selective anticancer activity in different cancer cell lines. Additive therapeutic action of the combination therapy of 4e and 4h was observed on lung cancer cells that overexpress both these isozymes. Further, 4e formed implantable self-assembled hydrogels that achieved sustained and selective killing of cancer cells in the vicinity of implantation.

Hogg, Robert W. (University of Illinois, Urbana), Chitra S. Biswas, and Harry P. Broquist. Interference with valine and isoleucine biosynthesis by cyclic hydroxamic acids. J. Bacteriol. 90:1265-1270. 1965.-The introduction of a hydroxyl group in a number of common barbiturates, a substitution which converts these compounds to cyclic hydroxamic acids, gives rise to compounds which inhibit growth of Escherichia coli. The toxicity of these hydroxybarbiturates appears to be associated, at least in part, with interference with valine and isoleucine biosynthesis, as a combination of these amino acids counteracts their toxicity. A subinhibitory level of 1-hydroxy-5-ethyl-5-isopropylbarbituric acid (hydroxyipral) was counteracted either by valine or by its early precursor, alpha-acetolactate, and led to a study of the effect of these cyclic hydroxamic acids on acetolactate synthesis in a cell-free enzyme system of E. coli. In this system, the parent barbiturates and their respective hydroxy derivatives were only moderately active in blocking acetolactate synthesis. Detailed kinetic studies of the most active compound, hydroxyipral showed no obvious relationship to the substrate or cofactors of the system. The inhibitory effects of hydroxyipral, either on growth of E. coli or in the acetolactate-forming system, could not be counteracted by Fe(++), but the toxic effect of aspergillic acid and o-phenanthroline in these instances was reversed by Fe(++), which implies an iron involvement in the acetolactate-forming system of E. coli.