DNA binding studies of site-specific minor groove binders
Presentation
Overview
Overview
Description
Compounds are being developed in our laboratory that can deliver cytotoxic, non-mutagenic DNA damage to targeted cells. One strategy that is being used is to combine together a compound known to produce exclusively N3-methyladenine DNA adducts with glucose amine in order to target the DNA-methylating compound to cells expressing specific glucose transporters. These new compounds contain a bis-pyrrole triamide unit that can bind specifically to the minor groove of DNA at A/T rich regions. Tethered to one side of this bis-pyrrole unit is a methyl sulfonate that will methylate the DNA, and to the other end is a glucose unit that is expected to provide selective transport into targeted cells. The site-specific DNA binding of these new compounds is essential for the achieving the desired DNA-damage in the targeted cells. The goal of this project is to investigate the DNA binding properties of these new molecules in thermodynamic studies using the duplex DNA decamer 5’-GCGAATTCGC-3’. For these studies, surrogate stable analog molecules have been synthesized in which the methyl sulfonate unit has been replaced by a stable methyl sulfone unit. Three different molecules, varying in the composition of the linker connecting the DNA-binding unit with the glucose unit, have been synthesized. The interactions of these molecules with the decamer have been investigated using differential scanning calorimetry (DSC). This paper presents the design of these compounds, the details of the syntheses, and the results of the thermodynamic studies.
