title: Inhibition of transcription factor-DNA complexes and gene expression by a microgonotropen.
abstract: 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 with positively charged, major groove-contacting side chains yields microgonotropens (MGTs). Previously, we demonstrated that MGTs were superior inhibitors of TF/DNA complexes in cell-free assays compared with "classical" groove binders, but MGTs showed limited ability to inhibit gene expression. To determine what chemical characteristics contribute to or improve activity, we evaluate five MGTs for their effectiveness in inhibiting TF complex formation and resultant transcription by using the c-fos serum response element (SRE) as a target. MGT L1 binds DNA via a bisbenzimidazole equipped with a tripyrrole moiety. It is compared with analog L2, which has been functionalized with propylamines on each of the three pyrroles. L2, which binds DNA at subpicomolar concentrations, was at least three orders of magnitude more potent than L1 at inhibiting TF binding to the c-fos SRE in cell-free assays. Unlike L1 and previous MGTs, L2 also inhibited endogenous c-fos expression 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 assays, its bisbenzimidazole moiety appears to impart improved cellular uptake and activity. These findings make L2 a promising lead candidate for future, rational MGT design.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: White
authors.forename: A L
authors.initials: AL
authors.lastname: Satz
authors.forename: T C
authors.initials: TC
authors.lastname: Bruice
authors.forename: T A
authors.initials: TA
authors.lastname: Beerman
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002474:Cell-Free System; D004247:DNA / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004214:Distamycins / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D026362:Serum Response Factor; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001562:Benzimidazoles; D004268:DNA-Binding Proteins; D004214:Distamycins; D008024:Ligands; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D011758:Pyrroles; D026362:Serum Response Factor; C437884:microgonotropen L2; D004247:DNA