New perspectives in oral peptide delivery.

Owing to their structural diversity, peptides are a unique source of innovative active ingredients. However, their development has been challenging because of their disadvantageous pharmacokinetic (PK) properties. Over the past decade, many attempts have been made to improve the oral bioavailability of peptide drugs.

Substituted pyrazolo[3,4-b]pyridines as human A1 adenosine antagonists: developments in understanding the receptor stereoselectivity.

A(1) adenosine receptor antagonists have been proposed to possess an interesting range of potential therapeutic applications. We have already reported the synthesis and the biological characterization of a family of pyrazolo[3,4-b]pyridine derivatives as A(1) adenosine ligands endowed with an antagonistic profile. In the present work, we report the LC separation of enantiomers of our most active A(1) antagonists together with the determination of their absolute configuration by means of X-ray crystal structure analysis.

2-Hydroxypropyl-β-cyclodextrin strongly improves water solubility and anti-proliferative activity of pyrazolo[3,4-d]pyrimidines Src-Abl dual inhibitors.

The main aim of this study was to enhance the solubility of pyrazolo[3,4-d]pyrimidines 1-8 able to strongly inhibit Src and Abl tyrosine kinase phosphorylation in cell-free assays and to significantly reduce leukemic and osteosarcoma cell lines growth, but characterized by very low solubility in aqueous media. Their water solubility was improved between 100 and 1000 folds by solubilization with 2-hydroxypropyl-β-cyclodextrin (HPβCD) and ratio of inclusion complex were determined by phase solubility method. Finally, some complexed compounds were tested on different leukemic (K-652, KU-812 and HL-60) and osteosarcoma (SaOS-2) cell lines showing a good enhancement of biological response in comparison with the not complexed compounds.

Synthesis of new linear guanidines and macrocyclic amidinourea derivatives endowed with high antifungal activity against Candida spp. and Aspergillus spp.

New linear and cyclic guanidines were synthesized and tested in vitro for their antifungal activity toward clinically relevant strains of Candida species, in comparison to fluconazole. Macrocyclic compounds showed a minimum inhibitory concentration in the micromolar range and a biological activity profile in some cases better than that of fluconazole. One macrocyclic derivative was also tested against Aspergillus species and showed high antifungal activity comparable to that of amphotericin B and itraconazole.

Synthesis and biological evaluation of guanidino compounds endowed with subnanomolar affinity as competitive inhibitors of maize polyamine oxidase.

Previous studies on agmatine and its derivatives suggested that the presence of hydrophobic groups on the guanidine moiety was a crucial key for inhibitory activity of maize polyamine oxidase. Accordingly, new lipophilic agmatine and iminoctadine derivatives were synthesized and tested for their ability to inhibit this enzyme. Several compounds showed an affinity in the nanomolar range, while a cyclopropylmethyl derivative of iminoctadine was found to be the most potent inhibitor of maize polyamine oxidase reported so far (Ki = 0.

Determination of permeability and lipophilicity of pyrazolo-pyrimidine tyrosine kinase inhibitors and correlation with biological data.

A library of 23 pyrazolo-pyrimidine compounds Src tyrosine kinase (TK) inhibitors, that reduced proliferation of a human osteogenic sarcoma cell line, was taken to investigate lack of correlation between inhibition of cellular viability (CV%) and enzymatic inhibition constants (K(i) Src). With the aim of understanding this behaviour, we focused on physico-chemical parameters which characterize partition coefficient and diffusion through membrane. Parallel artificial membrane permeability assay (PAMPA) has been frequently used for the evaluation of in vitro permeability of new chemical entities and, in this paper, a new approach for determining permeability of low soluble compounds was obtained.

Substituted pyrazolo[3,4-b]pyridines as potent A1 adenosine antagonists: synthesis, biological evaluation, and development of an A1 bovine receptor model.

Sixty-eight new substituted pyrazolo[3,4-b]pyridine derivatives were synthesized and tested for enriching a library of active A(1) adenosine receptor (AR) antagonists belonging to the same class. These compounds were also used as an external test set to check the reliability of a 3D QSAR model recently reported by us. To investigate the binding mode of pyrazolopyridine derivatives, a model of the bovine A(1)AR (bA(1)AR) was developed by a novel homology modeling approach and used to evaluate the main interactions of the ligands with the receptor through docking studies.

LC/ESI/MS method for the quantitative detection of guazatine residues in cereals.

Guazatine is a fungicide used in agriculture to control a wide range of seed-borne diseases of cereals and other vegetable foods. In this work, a LC-ESI-MS method was developed for the quantitative detection of guazatine residues in maize and hard wheat. Quantitative data were determined for the residues of the main diamines, triamines, and tetramines that cover more than 87% of the total contents of the mixture.

Analysis of guazatine mixture by LC and LC-MS and antimycotic activity determination of principal components.

Guazatine is a non-systemic contact fungicide, a mixture of reaction products from polyamines, comprising mainly octa-methylenediamine, iminodi(octamethylene)diamine, octamethylenebis(imino-octamethylene) diamine and carbamonitrile. In this work, the analysis of guazatine mixture by LC and LC-MS has been treated for the first time. In the guazatine mixture diamine derivatives account for 40% of the constituents of guazatine, triamines for 46%, tetramines for 11% and other amine derivatives for 3%.