Synthesis, Structural Characterization, and Biological Activity of New Pyrazolo[4,3- e][1,2,4]triazine Acyclonucleosides

Abstract

A series of new pyrazolo[4,3-e][1,2,4]triazine acyclonucleosides 2-5 and 8 were prepared and evaluated for their anticancer activity against human cancer cell lines (MCF-7, K-562) and CDK2/E, as well as Abl protein kinases inhibitors. Lipophilicity of the compounds was determined using C-18 and immobilized artificial membrane (IAM) chromatography. In order to confirm the molecular structures and synthesis pathway of new acyclonucleosides, X-ray analysis was performed for model compound 3. Theoretical calculations at the DFT/B3LYP/6-311++G(d,p) level were used for the characterization of electronic structures of 1-8. The potential antiviral activity of acyclonucleosides 2-8 was tested in silico using molecular docking method.

Keywords: X-ray analysis; acyclonucleosides; anticancer activity; molecular docking; pyrazolo[4,3-e][1,2,4]triazine; theoretical calculation.

Figure 1

Known acyclonucleosides.

Scheme 1

Synthetic pathway to pyrazolo[4,3-e][1,2,4]triazine acyclonucleosides.

Figure 2

UV–Vis spectra of compounds 1 and 2 in aqueous methanol solution of different pH values.

Figure 3

A view of the molecule (3), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 4

The molecules 1–8 with the vectors of dipole moment in the low-energy conformation obtained from calculations at the DFT/B3LYP/6-311++G(d,p) level.

Figure 5

A view of the interaction of (a) 8 and (b) Ac with amino acids of binding site in TK.