“Dynamical Docking” of Cyclic Dinuclear Au(I) Bis-N-heterocyclic Complexes Facilitates Their Binding to G-Quadruplexes

Abstract

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 compounds' stabilization properties toward G4s of different topologies of physiological relevance. Initial structure−activity relationships have been identified and recognize the family of xanthine derivatives as those more selective toward G4s versus duplex DNA. The binding modes and freeenergy 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.

Gold Complexes in Anticancer Therapy: From New Design Principles to Particle‐Based Delivery Systems

“…[191] In another work, the use of dimeric cyclic analogues of AuTMX 2 did not show stabilization improvements compared to the monomeric benchmark compound, but proved to be beneficial in the case of benzimidazole-based NHCs, although the obtained dimers are less selective than AuTMX 2 . [192]…”

“…Recent efforts to tune the ligand structure have revealed the importance of an uncrowded xanthine structure for efficient binding to various G4 units, and it has been shown that functionalization of N9 or N1 reduces G4 affinities when compared to the methylated adduct AuTMX 2 [191] . In another work, the use of dimeric cyclic analogues of AuTMX 2 did not show stabilization improvements compared to the monomeric benchmark compound, but proved to be beneficial in the case of benzimidazole‐based NHCs, although the obtained dimers are less selective than AuTMX 2 [192] …”

A Golden Touch in the Design of Porphyrin Metallacages as Multifaceted Anticancer Agents

“…Instead, a number of possibilities were identified in close energetic proximity. As previously observed in the case of other G4 stabilizers, [23,24] the true binding pose can be a combination of orientations that can spontaneously occur due to the low saddle points found between minima, allowing oscillations around a global minimum. Therefore, the overall average GMetaD was calculated at -31.9 ± 4.5 kJ•mol -1 .…”

“…[17][18][19][20] For instance, gold compounds do not only target proteinsincluding enzymes related to redox homeostasis, DNA repair systems and membrane proteins involved in water/small molecule transport [21,22] but can also act via non-covalent interactions, stabilizing non-canonical DNA secondary structures such as guanine-quadruplexes (G4s). [23,24] The latter are abundant in telomers and in promoter regions of oncogenes, and their stabilization has been proposed as a viable strategy towards anticancer therapy. [25][26][27] Despite these intriguing properties, and although several examples of gold-based metallacages structures have been reported, [28][29][30][31][32][33][34] only a handful of them have been studied to encapsulate small molecules.…”

Novel half Salphen cobalt(iii) complexes: synthesis, DNA binding and anticancer studies

“…The stability of the cobalt(III) Schiff bases, 1 and 2, was investigated via 1 H NMR in a mixture of D 6 -DMSO : D 2 O (80 : 20), following literature described protocols. 38,39 As shown in Fig. S14 and S15, † the spectra of both complexes showed no change over 24 h. As a key step in the compound formation was the oxidation of the metal center to the +3 state, we attempted to expose 1 and 2 to a physiologically relevant concentration of a representative biological reducing agent, the glutathione (GSH) tripeptide, thus assessing the capability of the compounds to revert to their oxidation state.…”