NEW SULFONYL PYRIMIDINES INDUCE APOPTOSIS THROUGH DNA CLEAVAGE PATHWAY

Priyanka Yadav, Shafia Mir, Praveen Kumar and Ayaz Mahmood Dar*

ABSTRACT

The new sulfonyl pyrimidinones (4-6) were synthesized by the reaction of sulfonyl thiosemicarbazones (1-3) with ethyl cyanoacetate in absolute ethanol. After characterization by spectral and analytical data, the DNA interactions of the compounds were carried out by UV-vis, fluorescence spectroscopy, circular dichroism, molecular docking and gel electrophoresis. The compound binds to DNA preferentially through electrostatic interactions with Kb; 2.93 ×103 M–1, 3.03 × 103 M–1 and 3.11 × 103 M–1, respectively depicting the higher propensity of compound 6 with CT DNA. Gel electrophoresis depicted that compound 6 brought conversion of SC form (Form II) into LC form (Form III) of DNA at 4.0 μM. The docking study suggested that the intercalation of compounds in between the nucleotide base pairs is due to the pyrimidinone moiety of the sulfone derivative. The circular dichroism studies suggest that compounds (4-6) affect the helicity of B-DNA. During in vitro cytotoxicity, compound (4-6) revealed potential toxicity against the different human cancer cells. AO/EB staining analysis clearly indicates that compound 5 causes apoptosis in cancer cells. The results revealed that compound 5 has better prospectus to act as a cancer chemotherapeutic candidate, which warrants further in vivo anticancer investigations.

Keywords: Sulfonyl pyrimidinones, Thiosemicarbazones, DNA binding, MTT.