A New Design Strategy and Diagnostic to Tailor the DNA-Binding Mechanism of Small Organic Molecules and Drugs

Abstract

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.

Specific Recognition of G-Quadruplexes Over Duplex-DNA by a Macromolecular NIR Two-Photon Fluorescent Probe

“…To assess and understand the binding mode of Ant-PIm toward 1 the methodology recently developed by Goodson and co-workers was used. , Their model relates the changes in the dye transition dipole moment to its orientation with respect to the DNA axis. As depicted in Figure B, similarly to linear absorption, the magnitude of the TPA cross-section is consistently reduced by the addition of quadruplex 1 regardless of the presence of metal ions in solution consistent with an intercalative binding process.…”

Efficient Singlet Oxygen Generation in Metal Nanoclusters for Two-Photon Photodynamic Therapy Applications

“…The control experiment confirms that cell death is triggered by PDT with the nanoclusters because the cells remain intact after excitation in the absence of the nanoclusters. The effective PDT by two-photon excitation is due to the high two-photon absorption cross section of metal nanoclusters (σ = 4 × 10 5 GM) compared to conventional photosensitizers (e.g., NMB, σ = 7 GM). , Due to the superior spatial resolution and sensitivity of two-photon absorption, and the high 1 O 2 generation rate of metal nanoclusters, PDT by two-photon excitation with nanoclusters enables deep tissue imaging, fine control over exposure area, and efficient treatment. − …”

Electrochemical, spectroscopic, and molecular docking studies of the interaction between the anti-retroviral drug indinavir and dsDNA

“…Small organic molecules can interact with DNA through groove binding, intercalation, and/or cross-linking (covalent bonding). Complex formation between small organic molecules and DNA through covalent binding or non-covalent interactions results in changes in the functional properties and thermal stability of DNA [ 12 ]. Often, such changes have a great impact on physiological functions.…”

“…Groove binding does not require unwinding of the DNA helical axis. Typically, groove binders prefer to bind at AT-rich sequences because GC-rich sequences contain a –NH 2 group that sterically inhibits binding [ 12 , 13 ].…”