A New Design Strategy and Diagnostic to Tailor the DNA-Binding Mechanism of Small Organic Molecules and Drugs.
The classical model for DNA groove binding states that groove binding molecules should adopt a crescent shape that closely matches the helical groove of DNA. Here, we present a new design strategy that does not obey this classical model. The DNA-binding mechanism of small organic molecules was investigated by synthesizing and examining a series of novel compounds that bind with DNA. This study has led to the emergence of structure-property relationships for DNA-binding molecules and/or drugs, which reveals that the structure can be designed to either intercalate or groove bind with calf thymus dsDNA by modifying the electron acceptor properties of the central heterocyclic core. This suggests that the electron accepting abilities of the central core play a key role in the DNA-binding mechanism. These small molecules were characterized by steady-state and ultrafast nonlinear spectroscopies. Bioimaging experiments were performed in live cells to evaluate cellular uptake and localization of the novel small molecules. This report paves a new route for the design and development of small organic molecules, such as therapeutics, targeted at DNA as their performance and specificity is dependent on the DNA-binding mechanism.
Department of Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
Phi
P
Doan
Department of Chemistry, University of Miami , Coral Gables, Florida 33146, United States.
Demar R G
DR
Pitter
Department of Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
Andrea
A
Kocher
Department of Chemistry, University of Miami , Coral Gables, Florida 33146, United States.
James N
JN
Wilson
Department of Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
Theodore
T
Goodson
D000818:Animals; D002417:Cattle; D004247:DNA / Q000737:chemistry*; D015195:Drug Design; D009930:Organic Chemicals / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet
D009930:Organic Chemicals; D004364:Pharmaceutical Preparations; D004247:DNA