Intramolecular Metal-Free N-N Bond Formation with Heteroaromatic Amines: Mild Access to Fused-Triazapentalene Derivatives.

Formation of N-N bonds may offer an original approach to various nitrogen-containing heterocycles with numerous applications. For this purpose, we found that readily available heteroaromatic amines are appropriate substrates for providing an efficient and innovative approach for the formation of N-N bonds in the presence of iodine (III) reagent in very mild conditions. This method makes it possible to synthesize nitrogen rich triazapentalene derivatives exhibiting fluorescent properties, inaccessible with existing approaches.

Physico-analytical studies on some heterocyclic azo dyes and their metal complexes with some transition metals.

In this investigation, the azo dyes; 2-(3'-phenyl-5'-pyrazolyl azo) schaffer acid (la) and 2-(3'-phenyl-5'-pyrazolyl azo) resorcinol (Ib); were prepared through diazotizing 3-phenyl-5-aminopyrazole (PAP) and coupling the resulting diazonium salt with Schäffer acid and resorcinol respectively. The prepared azo dyes are characterized using both IR spectra and the elemental analysis (C, H, N and S). The prepared azo dyes are used as chromogenic reagents for the spectrophotometric determination of copper (II), nickel (II), cobalt (II) and zinc (II) ions. The conditional acid dissociation constants of these azo dyes (la and Ib) and the stability constants of its metal ion complexes have been determined by spectro-analytical methods. The effect of pH, time, organic solvent and the foreign ions on the spectrophotometric determination of these ions and their complexes with the azo dyes under study were studied. The stoichiometric ratio (M:L) of the formed complexes was also determined. The molar absorptivity, the Sandell's sensitivity values, the obeyance of Beers law and the stability constants of the formed complexes have been also determined and discussed.

Aryl H-phosphonates. 19. New anti-HIV pronucleotide phosphoramidate diesters containing amino- and hydroxypyridine auxiliaries.

We have designed a new type of AZT and ddU phosphoramidate diesters containing various combinations of 2-, 3-, 4-aminopyridine and 2-, 3-, 4-hydroxypyridine moieties attached to the phosphorus center, as potential anti-HIV pronucleotides. Depending on the pKa values of the aminopyridines and the hydroxypyridines used, alternative synthetic strategies based on H-phosphonate chemistry were developed for their preparation. Synthetic aspects of these transformations and the biological activity of the synthesized compounds are discussed.

Beware of External Validation! - A Comparative Study of Several Validation Techniques used in QSAR Modelling.

BACKGROUND: Proper validation is an important aspect of QSAR modelling. External validation is one of the widely used validation methods in QSAR where the model is built on a subset of the data and validated on the rest of the samples. However, its effectiveness for datasets with a small number of samples but a large number of predictors remains suspect. OBJECTIVE: Calculating hundreds or thousands of molecular descriptors using currently available software has become the norm in QSAR research, owing to computational advances in the past few decades. Thus, for n chemical compounds and p descriptors calculated for each molecule, the typical chemometric dataset today has a high value of p but small n (i.e. n << p). Motivated by the evidence of inadequacies of external validation in estimating the true predictive capability of a statistical model in recent literature, this paper performs an extensive and comparative study of this method with several other validation techniques. METHODOLOGY: We compared four validation methods: Leave-one-out, K-fold, external and multi-split validation, using statistical models built using the LASSO regression, which simultaneously performs variable selection and modelling. We used 300 simulated datasets and one real dataset of 95 congeneric amine mutagens for this evaluation. RESULTS: External validation metrics have high variation among different random splits of the data, hence are not recommended for predictive QSAR models. LOO has the overall best performance among all validation methods applied in our scenario. CONCLUSION: Results from external validation are too unstable for the datasets we analyzed. Based on our findings, we recommend using the LOO procedure for validating QSAR predictive models built on high-dimensional small-sample data.

Mutagenicity of heteroaromatic amines: Computational study on the influence of methyl substituents.

Quantum mechanical calculations were performed to elucidate the factors determining the variations in mutagenic activity within groups of isomeric heteroaromatic amines that differ in the position of methyl substituents. Formation energies for noncovalent complexes and covalent DNA adducts were evaluated by means of high level quantum chemical methods. According to the computational results in this work, covalent adduct stability is proposed to influence the relative mutagenicities of structurally related heterocyclic amines. The stability of covalent C8-dG DNA adducts was found to be mainly determined by π-stacking interactions between the fused ring system of the heteroaromatic amines and the flanking nucleobases. Relative mutagenicity of amines of very related structure is proposed to be regulated by both nitrenium ion and covalent adduct stabilities.