Macromolecular Uptake of Alkyl‐Chain‐Modified Guanidinoglycoside Molecular Transporters

Abstract

Soothes your nerves: The enantiomerically enriched cis‐1,2‐dihydrocatechol 4 has been converted, over 16 steps including one involving an intramolecular Diels–Alder reaction, into the sesquiterpenoid natural product khusiol (3), which is structurally related to the neurite outgrowth‐promoting natural product 11‐O‐debenzoyltashironin (1).

Dendrimeric Guanidinoneomycin for Cellular Delivery of Bio‐macromolecules

“…The synthetic strategy used is based on the reaction between isothiocyanate‐modified GNeo and PAMAM dendrimers, resulting in the clean formation of stable thiourea conjugates as previously exploited . Accordingly, GNeo‐isothiocyanate 4 was synthesized through an azide–alkyne “click” reaction between GNeo derivative 2 and hetero‐bifunctionalized oligo(ethylene glycol) linker 3 , prepared as reported in the Supporting Information (Schemes and S1).…”

“…Indeed, direct guanidinylation of natural aminoglycoside antibiotics afforded guanidinoglycosides, a class of guanidinium‐rich efficient molecular transporters . These delivery vehicles are intriguing for several reasons, the most powerful being: 1) unlike other guanidinium‐rich transporters, their cellular delivery occurs at nanomolar concentrations, 2) their uptake exclusively depends on the presence of heparan sulfate proteoglycans (HSPGs), 3) they have been shown to induce HPSG aggregation, which is an important step for endocytic entry, and 4) their efficiency depends on the valency of the carriers . The last point prompted us to investigate cooperativity in the cellular uptake of multimeric guanidinoglycosides conjugates.…”

On Guanidinium and Cellular Uptake

“… 47 This pathway can be altered by selective acylation of guanidinoneomycin-based transporters with long alkyl chains, which enhances the macromolecular cellular uptake with little or no heparan sulfate aggregation (Figure 6 ). 48 These findings suggest an alternative and distinct pathway involving hydrophobic interactions impacting membrane curvature while assisting the uptake.…”

Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities

“…35). 136 These conjugates were prepared to study the internalization mechanism(s) of amphiphilic guanidinoglycosides by cell-surface FRET analysis. Their syntheses began with Boc protection of all amino groups of NEO prior to azidation of the 5″-position to afford 198 .…”