Dinuclear monointercalating RuII complexes that display high affinity binding to duplex and quadruplex DNA

The DNA duplex binding properties of previously reported dinuclear Ru(II) complexes based on the ditopic ligands tetrapyrido[3,2-a:2',3'-c:3',2'-h:2',3'-j]phenazine (tppz) and tetraazatetrapyrido[3,2-a:2'3'-c:3',2'-l:2',3'-n]pentacene (tatpp) are reported. Photophysical and biophysical studies indicate that, even at high ionic strengths, these complexes bind to duplex DNA, through intercalation, with affinities that are higher than any other monointercalating complex and are only equalled by DNA-threaded bisintercalating complexes. Additional studies at high ionic strengths using the 22-mer d(AG(3)[T(2)AG(3)](3)) [G3] human telomeric sequence reveal that the dinuclear tppz-based systems also bind with high affinity to quadruplex DNA. Furthermore, for these complexes, quadruplex binding is accompanied by a distinctive blue-shifted "light-switch" effect, characterized by higher emission enhancements than those observed in the analogous duplex effect. Calorimetry studies reveal that the thermodynamics of duplex and quadruplex binding is distinctly different, with the former being entirely entropically driven and the latter being both enthalpically and entropically favored.     

An Organometallic Gold(I) Bis-N-Heterocyclic Carbene Complex with Multimodal Activity in Ovarian Cancer Cells

The organometallic Au^I bis-N-heterocyclic carbene complex [Au(9-methylcaffeine-8-ylidene)₂]⁺ ( AuTMX₂ ) was previously shown to selectively and potently stabilise telomeric DNA G-quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX₂ in the cellular context using mass spectrometry-based methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal-based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non-covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX₂ by alterations in the nucleolus, telomeres, actin stress-fibres and stress-responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.     

Molecular Recognition of the Hybrid‐2 Human Telomeric G‐Quadruplex by Epiberberine: Insights into Conversion of Telomeric G‐Quadruplex Structures

Human telomeres can form DNA G‐quadruplex (G4), an attractive target for anticancer drugs. Human telomeric G4s bear inherent structure polymorphism, challenging for understanding specific recognition by ligands or proteins. Protoberberines are medicinal natural‐products known to stabilize telomeric G4s and inhibit telomerase. Here we report epiberberine (EPI) specifically recognizes the hybrid‐2 telomeric G4 predominant in physiologically relevant K⁺ solution and converts other telomeric G4 forms to hybrid‐2, the first such example reported. Our NMR structure in K⁺ solution shows EPI binding induces extensive rearrangement of the previously disordered 5′‐flanking and loop segments to form an unprecedented four‐layer binding pocket specific to the hybrid‐2 telomeric G4; EPI recruits the (?1) adenine to form a “quasi‐triad” intercalated between the external tetrad and a T:T:A triad, capped by a T:T base pair. Our study provides structural basis for small‐molecule drug design targeting the human telomeric G4.