Inclusion complexes of a nucleotide analogue with hydroxypropyl-beta-cyclodextrin

• Published in: Journal of Inclusion Phenomena and Macrocyclic Chemistry Vol. 63; no. 1-2; pp. 11 - 16
• Main Authors: Jordheim, Lars Petter, Degobert, Ghania, Diab, Roudayna, Peyrottes, Suzanne, Périgaud, Christian, Dumontet, Charles, Fessi, Hatem
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01-02-2009; Springer Verlag
• Subjects: Chemistry; Chemistry and Materials Science; Crystallography and Scattering Methods; Food Science; Life Sciences; Organic Chemistry; Original Article; Pharmaceutical sciences; 2-Hydroxypropyl-beta-cyclodextrin; Pronucleotide; Deoxynucleoside analogues; Inclusion complexes; AraC; In vivo
• ISSN: 0923-0750; 1573-1111
• DOI: 10.1007/s10847-008-9483-8

Bis(
t
butyl-
S
-acyl-2-thioethyl)-AraCMP (UA911) is a mononucleotide prodrug developed to overcome some of the cellular resistance to cytotoxic deoxynucleosides analogues. Its use for in vivo studies is limited due to its poor solubility in water. Thus, 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) was proposed to solubilize UA911 in water, in order to obtain concentrations needed for in vivo experiments. A molar ratio of HP-β-CD: UA911 of 3:1 was sufficient to obtain complete solubilization of the prodrug. The corresponding inclusion complex was characterized by differential scanning calorimetry and
1
H NMR spectroscopy study provided a definitive proof of the formation of the inclusion complex. The complex retained its cytotoxic activity as shown by in vitro cell survival assays on murine leukemia cells, and was evaluated in vivo. HP-β-CD is therefore suitable for the preparation of adequate solutions for the study of the antitumoral activity of nucleotide prodrugs such as UA911.