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.
Dreassi
Elena
E
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.
Zizzari
Alessandra Tania
AT
Mori
Mattia
M
Filippi
Irene
I
Belfiore
Amalia
A
Naldini
Antonella
A
Carraro
Fabio
F
Santucci
Annalisa
A
Schenone
Silvia
S
Botta
Maurizio
M
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014867:Water / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D047392:beta-Cyclodextrins; D014867:Water; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C014175:pyrazolo(3,4-d)pyrimidine; D019061:src-Family Kinases