Dihydroimidazophenanthridinium (DIP)-based DNA binding agents with tuneable structures and biological activity.
We have synthesised a library of dihydroimidazophenanthridinium cations (DIPs) with large structural diversity (1-29) using a "one-pot" approach. The DNA binding constants of DIPs range from 2x10(4) to 1.3x10(5) M(-1), and the free energies for binding range from -5.9 to -6.40 kcal mol(-1). Viscosity measurements demonstrated that the binding of the compounds caused DNA lengthening, thus signifying binding by intercalation. The cytotoxicities of the compounds were determined by tetrazolium dye-based microtitration assays and showed a large range of values (0.09-11.7 microM). Preliminary molecular modelling studies of the DNA-DIP interactions suggested that the DIP moieties can interact with DNA by intercalation, and some R groups might facilitate binding by minor-groove binding. The results provide insight into how to design biologically active DNA binding agents that can interact in these ways.
Smith
Louise V
LV
WestCHEM Department of Chemistry, Joseph Black Building, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK.
Parenty
Alexis D C
AD
Guthrie
Kevin M
KM
Plumb
Jane
J
Brown
Robert
R
Cronin
Leroy
L
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D010617:Phenanthridines / Q000737:chemistry* / Q000633:toxicity*
D010617:Phenanthridines; D004247:DNA