Ring Tension Applied to Thiol‐Mediated Cellular Uptake

Abstract

The objective of the study was to explore the potential of ring tension in cyclic disulfides for thiol-mediated cellular uptake. Fluorescent probes that cannot enter cells were equipped with cyclic disulfides of gradually increasing ring tension. As demonstrated by flow cytometry experiments, uptake into HeLa Kyoto cells increased with increasing tension. Differences in carbon-sulfur-sulfur-carbon (CSSC) dihedral angles as small as 8° caused significant changes in uptake efficiency. Uptake with high ring tension was better than with inactivated or activated linear disulfides or with thiols. Conversion of thiols on the cell surface into sulfides and disulfides decreased the uptake. Reduction of exofacial disulfides into thiols increased the uptake of transporters with disulfides and inactivated controls with thiols. These results confirm the occurrence of dynamic covalent disulfide-exchange chemistry on cell surfaces. Mechanistic and colocalization studies indicate that endocytosis does not fully account for this cellular uptake with ring tension.

Epidithiodiketopiperazines: Strain-Promoted Thiol-Mediated Cellular Uptake at the Highest Tension

“…Contrary to AspA controls, 12,13 the removal of thiols on cell surfaces with maleimide 26 , 22 iodoacetamide 27 , 12 and the most powerful hypervalent iodine reagent 28 (29) failed to inactivate ETP 6 (Figure 4C). Similarly, the presence of 10% serum 22 caused only a minor ∼25% reduction of ETP uptake (Figures 4C and S5).…”

“…11 Uptake efficiencies were found to increase with ring tension from relaxed disulfides 3 with θ ≈ 90° to lipoic acid derivatives 4 with θ = 35° and asparagusic acid derivatives 5 with θ = 27°. 12,13 The most efficient “AspA tag” as in 5 allowed the delivery of functional peptides, 14 liposomes and polymersomes 13 into cells, and the transferrin receptor (TFRC) has been identified as one of the targets. 14 The power and promise of strain-promoted thiol-mediated uptake at θ = 27° provided a compelling incentive to drive disulfide ring tension to the extreme.…”

Crosslinked Redox‐Responsive Micelles Based on Lipoic Acid‐Derived Amphiphiles for Enhanced siRNA Delivery

“…It has already been shown that lipoic acid-based vesicles show remarkable polymerization/depolymerization properties, thereby offering a possible route to both effi ciently protect and release encapsulated entities. [50][51][52] Furthermore, their biological potential has been recently realized as unique motifs to trigger cellular uptake per se, so-called cell-penetrating poly(disulfi de)s, [53][54][55] which show noteworthy delivery profi les; [56] thus underlining the outstanding suitability of lipoic acid entities for drug and gene delivery applications. [57][58][59][60] All building blocks were selected in that they represent nontoxic entities in order to preferably generate biocompatible gene carriers that additionally, after successful nucleic acid delivery, do not raise toxic effects following intracellular fragmentation.…”

Cell‐Penetrating Dynamic‐Covalent Benzopolysulfane Networks

“…[5] Benzopolysulfane rings are not very strained (XSSX dihedral angles ! [1][2][3][4][5][6][7] This extreme sulfur chemistry attracted our attention in our search for new ways to enter cells.F rom cell-penetrating peptides (CPPs) [8] to cell-penetrating poly(disulfide)s (CPDs) [9] and COCs, [10][11][12][13] the cellular uptake via dynamic covalent dichalcogenide exchange chemistry has come to prominence,o ften referred to as thiol-mediated uptake,w ith exofacial thiols as initial targets and continuing on the way into the cell. [1][2][3][4][5][6][7] This extreme sulfur chemistry attracted our attention in our search for new ways to enter cells.F rom cell-penetrating peptides (CPPs) [8] to cell-penetrating poly(disulfide)s (CPDs) [9] and COCs, [10][11][12][13] the cellular uptake via dynamic covalent dichalcogenide exchange chemistry has come to prominence,o ften referred to as thiol-mediated uptake,w ith exofacial thiols as initial targets and continuing on the way into the cell.…”

“…728 8), [6] but excel with unique,complex chemistry. [10][11][12][13][14][15] Promising results with strained cyclic disulfides [10,11] and diselenides [12,13] called for as hift of attention to the extreme sulfur chemistry of higher oligochalcogenides. [10][11][12][13][14][15] Promising results with strained cyclic disulfides [10,11] and diselenides [12,13] called for as hift of attention to the extreme sulfur chemistry of higher oligochalcogenides.…”