New betulin imine derivatives with antioxidant and selective antitumor activity

Abstract

Betulin is a naturally originating terpenoid, which attracted the attention of researchers due to its bioactive properties, including antitumor activity. This paper reports new betulin-imine derivatives, their synthesis, structural characterization and investigation of their antioxidant and anticancer activities. To this aim, a betulin aldehyde has been firstly prepared via an oxidation reaction using a Tempo reagent, which was further reacted with a series of aliphatic amines via an acid condensation reaction. The proposed chemical structures were confirmed using ¹H-NMR and FTIR spectroscopy and single crystal X-ray diffraction, and characterized by solubility tests, ultraviolet-visible (UV-Vis) and photoluminescence spectroscopy, thermogravimetric analysis and polarized light microscopy. All the compounds were easily soluble in common organic solvents, and showed good thermal stability. They showed strong birefringence under polarized light indicating their crystalline nature, which was attributed to single crystal diffraction and they belong to the Sohnke P2₁2₁2₁ space groups. The investigation of optical properties using photoluminescence spectroscopy revealed that all the imines emitted blue light in solution and in the solid state. The DPPH radical scavenging test showed that the antioxidant activity of betulin was significantly improved by imination with the increase of the aliphatic chain length. The antitumor activity investigated in vitro using the MTS assay on human breast cancer cell line MCF-7 (adenocarcinoma) and on non-tumorigenic epithelial cell line MCF-10A showed that the betulin-imine derivatives have improved antitumor activity and selectivity compared to neat betulin, suggesting that a medium length of the alkyl chain is favorable for the antiproliferative activity.