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.

Phase solubility studies were conducted for a class of very insoluble pyrazolo-pyrimidines and for their complexes with HPβCD. Increased solubility observed for all compounds, together with the very significative improvement of their biological activity, set the bases for enhancing the bioavailability of these promising candidate-drugs.Figure optionsDownload as PowerPoint slide