Inhibition of transcription factor-DNA complexes and gene expression by a microgonotropen

Developing minor groove-binding drugs to selectively inhibit transcription factor (TF)/DNA interactions and accompanying gene expression is a current goal in drug development studies. Equipping minor groove-binding agents wit h positively charged, major groove-contacting side chains yields microgonot ropens (MGTs). Previously, we demonstrated that MGTs were superior inhibito rs of TF/DNA complexes in cell-free assays compared with "classical" groove binders, but MGTs showed limited ability to inhibit gene expression. To de termine what chemical characteristics contribute to or improve activity, we evaluate five MGTs for their effectiveness in inhibiting TF complex format ion and resultant transcription by using the c-fos serum response element ( SRE) as a target. MGT Ll binds DNA via a bisbenzimidazole equipped with a t ripyrrole moiety. It is compared with analog L2, which has been functionali zed with propylamines on each of the three pyrroles. L2, which binds DNA at subpicomolar concentrations, was at least three orders of magnitude more p otent than L1 at inhibiting TF binding to the c-fos SIRE in cell-free assay s. Unlike Li and previous MGTs, L2 also inhibited endogenous c-fos expressi on in NIH 3T3 cells at micromolar levels, Structure/activity relationships suggest that, although the tripyrrole/polyamine functional group of L2 may be largely responsible for its inhibition of TF complexes in cell-free assa ys, its bisbenzimidazole moiety appears to impart improved cellular uptake and activity. These findings make L2 a promising lead candidate for future, rational MGT design.