A semi-empirical Hückel molecular orbital analysis of internucleotide phosphorothioate diesters

Oligonucleotides that contain internucleotide phosphorothioate diesters have potential as anticancer therapeutic agents through sequence-specific antisense mechanisms. Although the chemical reactivity of internucleotide phosphorothioate diesters has been utilized to form phosphorothioate oligonucleotide conjugates, the theoretical basis for this chemical reactivity needs further elucidation. Calculations reported here, performed by the Huckel molecular orbital method, show that the energy of the highest occupied molecular orbital (HOMO) of the internucleotide phosphorothioate diester is 15.9 kcal/mole higher than that of the corresponding HOMO of the internucleotide phosphate diester. The electron density in the phosphorothioate HOMO is almost completely centered on the sulfur atom. The results of this parametricized Huckel molecular orbital analysis are consistent with the model of the internucleotide phosphorothioate sulfur as a soft nucleophile.