Design, Synthesis, and Binding Affinity Evaluation of Hoechst 33258 Derivatives for the Development of Sequence-Specific DNA-Based Asymmetric Catalysts

Abstract

To date, the concept of DNA-based asymmetric catalysis has been successfully applied to various synthetic transformations by way of hybrid catalysts involving either an intercalator or an integrated ligand anchored through supramolecular interactions. We report here a new anchoring strategy based on the well-known groove-binder Hoechst 33258. The interaction between calf thymus DNA (ct-DNA) and poly­[d­(A-T)2] with a series of Hoechst 33258-derived ligands was studied by UV–vis absorption spectroscopy, thermal melting analysis, fluorescence emission, CD spectroscopy, mass spectrometry, and molecular docking. The results clearly show that a groove-binding anchoring strategy can be envisioned for DNA-based asymmetric catalysis, offering additional mechanistic insight on how the intrinsic chirality of DNA can be transferred to a reaction product. Most importantly, this new anchoring strategy offers interesting compartmentalization possibilities and provides a new way to reverse the enantioselectivity outcome of a given reaction.

From Interaction to Function in DNA‐Templated Supramolecular Self‐Assemblies

“…Here it is the chiral transfer from the DNA template to the catalyst that is of interest for asymmetric catalysis, as sketched in Figure (for reviews of the field, see for instance references). Supramolecular anchoring of the catalysts within the DNA template can be achieved by using specific ligands which will direct DNA binding through intercalation or groove binding, possibly with sequence selectivity . Precise positioning is key to optimize transfer of chiral information from the template to the catalyst …”

The Use of Hoechst Dyes for DNA Staining and beyond

“…However, Hoechst 33258 is still the most commonly used dye for DNA staining and as a starting compound for the synthesis of more complex sensors or probes. It possesses a phenolic (-OH) group, which can be used for the attachment of the linker by standard Williamson ether synthesis conditions or can be readily transformed to triflate and further coupled to a moiety of interest by a transition metal catalysed cross-coupling reaction [28].…”

α,β‐Unsaturated 2‐Acyl‐Imidazoles in Asymmetric Biohybrid Catalysis

“…Hence, instead of evaluating the sequence dependency of a given reaction, we envisioned to design sequence‐specific catalysts. The well‐known minor groove binder Hoechst‐33258, recognized for its strong affinity for AT‐rich regions of DNA, was selected and modified to incorporate a Cu(II) binding site (Figure ) …”

“…The well-known minor groove binder Hoechst-33258, recognized for its strong affinity for AT-rich regions of DNA, was selected and modified to incorporate a Cu (II) binding site ( Figure 14). [56] Among all the ligands that were synthesized and evaluated in the Cu(II)-catalysed Friedel-Crafts alkylation of α,β-unsatu-rated 2-acyl imidazole 8 with 5-methoxyindole 32, ligand L5 provided the best selectivities (up of 47 % ee with ct-DNA). Although moderate, higher selectivities were obtained with the ligand having the highest binding affinity with DNA, thus reinforcing a possible correlation between affinity and selectivity.…”