2 research outputs found
âDynamical Dockingâ of Cyclic Dinuclear Au(I) Bis-N-heterocyclic Complexes Facilitates Their Binding to GâQuadruplexes
With the aim to improve the design of metal complexes
as stabilizers
of noncanonical DNA secondary structures, namely, G-quadruplexes (G4s),
a series of cyclic dinuclear Au(I) N-heterocyclic carbene complexes
based on xanthine and benzimidazole ligands has been synthesized and
characterized by various methods, including X-ray diffraction. Fluorescence
resonance energy transfer (FRET) and CD DNA melting assays unraveled
the compoundsâ stabilization properties toward G4s of different
topologies of physiological relevance. Initial structureâactivity
relationships have been identified and recognize the family of xanthine
derivatives as those more selective toward G4s versus duplex DNA.
The binding modes and free-energy landscape of the most active xanthine
derivative (featuring a propyl linker) with the promoter sequence cKIT1 have been studied by metadynamics. The atomistic simulations
evidenced that the Au(I) compound interacts noncovalently with the
top G4 tetrad. The theoretical results on the Au(I) complex/DNA Gibbs
free energy of binding were experimentally validated by FRET DNA melting
assays. The compounds have also been tested for their antiproliferative
properties in human cancer cells in vitro, showing generally moderate
activity. This study provides further insights into the biological
activity of Au(I) organometallics acting via noncovalent interactions
and underlines their promise for tunable targeted applications by
appropriate chemical modifications
âDynamical Dockingâ of Cyclic Dinuclear Au(I) Bis-N-heterocyclic Complexes Facilitates Their Binding to GâQuadruplexes
With the aim to improve the design of metal complexes
as stabilizers
of noncanonical DNA secondary structures, namely, G-quadruplexes (G4s),
a series of cyclic dinuclear Au(I) N-heterocyclic carbene complexes
based on xanthine and benzimidazole ligands has been synthesized and
characterized by various methods, including X-ray diffraction. Fluorescence
resonance energy transfer (FRET) and CD DNA melting assays unraveled
the compoundsâ stabilization properties toward G4s of different
topologies of physiological relevance. Initial structureâactivity
relationships have been identified and recognize the family of xanthine
derivatives as those more selective toward G4s versus duplex DNA.
The binding modes and free-energy landscape of the most active xanthine
derivative (featuring a propyl linker) with the promoter sequence cKIT1 have been studied by metadynamics. The atomistic simulations
evidenced that the Au(I) compound interacts noncovalently with the
top G4 tetrad. The theoretical results on the Au(I) complex/DNA Gibbs
free energy of binding were experimentally validated by FRET DNA melting
assays. The compounds have also been tested for their antiproliferative
properties in human cancer cells in vitro, showing generally moderate
activity. This study provides further insights into the biological
activity of Au(I) organometallics acting via noncovalent interactions
and underlines their promise for tunable targeted applications by
appropriate chemical modifications