Synthesis of an Enlarged Library of Dynamic DNA Activators with Oxime, Disulfide and Hydrazone Bridges

Abstract

Dynamic amphiphiles have a "bridge" between their charged head and their hydrophobic tails. The presence of dynamic covalent bonds is of interest for differential and biosensing applications as well as for rapid access to the libraries needed to screen for gene delivery or cellular uptake of siRNA. However, efforts to develop libraries have so far concentrated on hydrazone bridges to monocationic heads. Here, we report synthesis efforts to enlarge this focused library with oxime and disulfide bridges and dynamic amphiphiles with more than one positive charge. Evaluation in fluorogenic vesicles reveals best activation of DNA as ion transporters by dynamic amphiphiles with dendritic scaffolds, doubly charged heads and four tails. Moreover, oximes, contrary to hydrazones, remain active under acidic conditions. Linear elongation of dendritic head-groups seems to cause increasing detergent effects and should therefore be avoided.

Dynamic Covalent Self‐Assembly Based on Oxime Condensation

“…Thed ynamic nature of hydra-zone,however, jeopardizes the inherent stabilities of the selfassembled products.F or example,w eo bserved that the catenanes [18,19] containing hydrazone undergo decomposition via hydrazone exchange during counteranion exchange or solvent removal, even in the condition of low temperature and/or in the absence of acid catalyst. Even although oxime condensation has already been employed in various fields such as bioconjugation, [24][25][26] and organic-inorganic ligation, [27] it is surprising to us that using oxime condensation as aDCC reaction motif for self-assembly of topologically complex molecules is not yet reported to the best of our knowledge. Protonation of NH 2 ,t os ome extent, suppresses the latter process leading to C = Nb ond formation.…”

“…Oxime, [21] namely -C= N À O-, is reported [22] to be more robust than hydrazone both thermodynamically and kinetically.T here are af ew reasons that can explain the enhanced stability of oxime compared to its hydrazone counterparts.F irst, the NH 2 unit in either the alkoxyamino (-OÀNH 2 )o rh ydrazide (-NHÀNH 2 )p recursor could undergo protonation in water, which could be considered as ac ompetitive process of nucleophilic addition. Even although oxime condensation has already been employed in various fields such as bioconjugation, [24][25][26] and organic-inorganic ligation, [27] it is surprising to us that using oxime condensation as aDCC reaction motif for self-assembly of topologically complex molecules is not yet reported to the best of our knowledge. In an alkoxyamino (-O-NH 2 )precursor,the NH 2 group is connected with amore electronegative oxygen atom compared to the nitrogen in hydrazide.T he NH 2 function in the former precursor is thus less protonated, and therefore -C=NÀO-bond formation is more favoured.…”

Oligothiophene Amphiphiles as Planarizable and Polarizable Fluorescent Membrane Probes

“…To assure the amphiphilicity needed for delivery, partitioning, and orientation in lipid bilayers, we envisioned a covalent capture strategy that has been introduced recently to prepare otherwise intractable molecules with unusual physical properties in situ, such as the final amphiphiles 1, 2, 4, and 5 (Scheme 1). [13] Monovalent, singly charged oximes and hydra- zones were selected to avoid complications from multivalency. Slight differences in length were considered irrelevant because, in action, these hydrophilic termini are expected to float freely above the lipid bilayer.…”

Tuning the Properties of Penetrating Peptides by Oxime Conjugation

“…For this purpose we prepared egg yolk phosphatidylcholine (EYPC) large unilamellar vesicles (LUVs) loaded with the anionic fluorophore 8-hydroxy-1,3,6-pyrenetrisulfonate (HPTS) and the cationic quencher p-xylene-bispyridinium bromide (DPX) (Figure 2). 23,24 In this assay, the intravesicular concentrations of dye (HPTS) and quencher (DPX) are balanced to afford minimal emission of the resting state vesicles (see Supporting Informa- …”