Structural Optimization of Azacryptands for Targeting Three-Way DNA Junctions.

Transient melting of the duplex-DNA (B-DNA) during DNA transactions allows repeated sequences to fold into non-B DNA structures, including DNA junctions and G-quadruplexes. These noncanonical structures can act as impediments to DNA polymerase progression along the duplex, thereby triggering DNA damage and ultimately jeopardizing genomic stability. Their stabilization by ad hoc ligands is currently being explored as a putative anticancer strategy since it might represent an efficient way to inflict toxic DNA damage specifically to rapidly dividing cancer cells. The relevance of this strategy is only emerging for three-way DNA junctions (TWJs) and, to date, no molecule has been recognized as a reference TWJ ligand, featuring both high affinity and selectivity. Herein, we characterize such reference ligands through a combination of in vitro techniques comprising affinity and selectivity assays (competitive FRET-melting and TWJ Screen assays), functional tests (qPCR and Taq stop assays), and structural analyses (molecular dynamics and NMR investigations). We identify novel azacryptands TrisNP-amphi and TrisNP-ana as the most promising ligands, interacting with TWJs with high affinity and selectivity. These ligands represent new molecular tools to investigate the cellular roles of TWJs and explore how they can be exploited in innovative anticancer therapies.

Switching between Nonisoenergetic Dynamic Covalent Reactions Using Host-Guest Chemistry.

CO2 reacts with simple amines in the presence of water to generate dynamic combinatorial libraries of majority (i.e., ammonium carbamates) and minority (i.e., ammonium carbonates) nonisoenergetic covalent adducts. Over the past two decades, our laboratory has reported on a new class of cavitands, namely, dyn[n]arenes, from which a polyanionic macrocycle is a highly efficient receptor for linear polyammoniums that forms [2]pseudorotaxanes in water at neutral pH. Herein, we demonstrate that the formation of [2]pseudorotaxanes shifts the equilibrium of CO2 capture by polyamines in water toward the quasi-exclusive formation of carbonate adducts, providing the first example of a switch between two competitive and reversible covalent processes triggered by host-guest interactions. In addition, this supramolecular approach to CO2 capture exhibits enhanced capture efficiency by increasing the state of protonation of complexed vs uncomplexed polyamines. Altogether, we report here that a templating approach can divert the outcome of two reversible covalent chemistries involving nucleophilic additions and acid-base reactions, challenging therefore the common knowledge that noncovalent and covalent bonds operate in separate energy frames.

Self-assembly of achiral building blocks into chiral cyclophanes using non-directional interactions.

The diastereoselective assembly of achiral constituents through a single spontaneous process into complex covalent architectures bearing multiple stereogenic elements still remains a challenge for synthetic chemists. Here, we show that such an extreme level of control can be achieved by implementing stereo-electronic information on synthetic organic building blocks and templates and that non-directional interactions (i.e., electrostatic and steric interactions) can transfer this information to deliver, after self-assembly, high-molecular weight macrocyclic species carrying up to 16 stereogenic elements. Beyond the field of supramolecular chemistry, this proof of concept should stimulate the on-demand production of highly structured polyfunctional architectures.