The tautomerism of some substituted 2-hydroxypyridines is investigated by UV/Vis-and 1 H-, and 13 C-NMR spectroscopic methods, with the aid of the N-Me and O-Me fixed parents. NMR spectroscopic data do not allow discrimination between the two tautomeric forms (with the exception of the unsubstituted 2-hydroxypyridine), while UV/Vis-data permit the quantitative determination, in different solvents, of the amounts of the two forms. The electronic substituent effect and the change of solvent are discussed. An X-Ray diffraction study carried out on a crystal of 2-hydroxy-5-nitropyridine (7) reveals that this compound, in the solid state, is in the oxo-form.

Recent studies have shown that an endogenous lipoperoxidation product, 9-hydroxystearic acid (9-HSA), acts in colon carcinoma cells (HT29) as a growth inhibitor by inducing p21 WAF1 in an immediate-early, p53-independent manner and that p21 WAF1 is required for 9-HSA-mediated growth arrest in HT29 cells. It is conceivable, therefore, to hypothesize that the cytostatic effect induced by this agent is at least partially associated with a molecular mechanism that involves histone deacetylase 1 (HDAC1) inhibition, as demonstrated for sodium butyrate and other specific inhibitors, such as trichostatin A and hydroxamic acids. Here, we show that, after administration, 9-HSA causes an accumulation of hyperacetylated histones and strongly inhibits the activity of HDAC1. The interaction of 9-HSA with the catalytic site of the enzyme has been highlighted by computational modeling of the human HDAC1, using its homolog from the hyperthermophilic Aquifex aeolicus as a template. Consistent with the experimental data, we find that 9-HSA can bind to the active site of the protein, showing that the inhibition of the enzyme can be explained at the molecular level by the ligand-protein interaction. Supplementary key words endogenous lipid peroxidation products • tumor • mass spectrometry • computational modeling 9-Hydroxystearic acid (9-HSA) belongs to the class of endogenous lipid peroxidation by-products that are greatly diminished in tumors and therefore become unable to exert their normal controlling functions on cell division (1). Indeed, in HT29 cells, exogenous administration of 9-HSA at micromolar concentrations results in a significant inhibition of proliferation rate as well as a significant increase of p53-independent p21 WAF1 expression (2). The expression of the cell cycle kinase inhibitor p21 WAF1 is induced in neoplastic cells by histone deacetylase 1 (HDAC1) inhibitors such as phenyl butyrate, sodium butyrate, trichostatin A (TSA), and suberoylanilide hydroxamic acid (SAHA). Increased expression of p21 WAF1 may play a critical role in the growth arrest induced in transformed cells by these agents, and it can be regulated, at least in part, by histone acetylation of the chromatin associated with the p21 WAF1 gene. Histone acetylation and gene activation induced by HDAC1 inhibitors would consequently be selective (3). The mode of action of 9-HSA is similar to that of HDAC inhibitors.Crystallographic studies performed using TSA and SAHA indicate that these compounds inhibit HDAC activity by interacting with the catalytic site, thereby blocking substrate access (4, 5). Short-chain fatty acids, such as phenyl butyrate and phenyl acetate, inhibit HDAC activity and affect the expression of numerous genes with disparate cellular functions (6)(7)(8). These agents have been tested in the clinic, but they suffer from a short plasma half-life as well as from the relatively high (millimolar) concentrations that are required for their action. On the other hand, hydroxamic acids such as TSA, SAHA, m -carboxycinnamic acid ...

Proposal accepted: NMR experiments have shown unequivocally that the previously only proposed zwitterionic carbon–carbon Meisenheimer–Wheland complexes are formed in the reaction of 4,6‐dinitrobenzofuroxan (DNBF) with 1,3,5‐tris(N,N‐dialkylamino)benzenes. Increasing the temperature results in a rapid exchange between three homomeric forms of the complex (see scheme; NR2=piperidyl, morpholinyl, pyrrolidinyl).

We have investigated reactions between 1,3,5‐tris(1‐piperidyl)benzene and 1,3,5‐tris(4‐morpholinyl)benzene and 4‐substituted arenediazonium tetrafluoroborate salts, mainly by NMR spectroscopic measurements. The main products are σ complexes (Wheland‐like intermediates) which are formed in almost quantitative yields and are moderately stable compounds. From these covalent complexes, products of the azo‐coupling reaction may be obtained as salts or as free bases. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

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