Cell‐Penetrating Dynamic‐Covalent Benzopolysulfane Networks

Abstract

Cyclic oligochalcogenides (COCs) are emerging as promising systems to penetrate cells. Clearly better than and different to the reported diselenolanes and epidithiodiketopiperazines, we introduce the benzopolysulfanes (BPS), which show efficient delivery, insensitivity to inhibitors of endocytosis, and compatibility with substrates as large as proteins. This high activity coincides with high reactivity, selectively toward thiols, exceeding exchange rates of disulfides under tension. The result is a dynamic‐covalent network of extreme sulfur species, including cyclic oligomers, from dimers to heptamers, with up to nineteen sulfurs in the ring. Selection from this unfolding adaptive network then yields the reactivities and selectivities needed to access new uptake pathways. Contrary to other COCs, BPS show high retention on thiol affinity columns. The identification of new modes of cell penetration is important because they promise new solutions to challenges in delivery and beyond.

Inhibitors of thiol-mediated uptake

“…Thiol-mediated uptake [1][2][3][4][5][6][7][8][9][10] has been developed to explain surprisingly efficient cellular uptake of substrates attached to thiol-reactive groups, most notably disuldes. The key step of this mechanism is the dynamic covalent thiol-disulde exchange between disuldes of the substrates and exofacial thiols on cell surfaces (Fig.…”

Artificial Metalloenzymes: From Selective Chemical Transformations to Biochemical Applications

“…In contrast, neither 107 alone nor 107 ·Sav(S112A) could turn on the T 3 -responsive gene switch. Subsequently, it was also demonstrated that the artificial deallylase 107 ·Sav could be introduced into HeLa cells by using different types of cell-penetrating cargo and could successfully show catalytic activity [ 137 , 138 ].…”

Naphthalenediimides with Cyclic Oligochalcogenides in Their Core

“…In 3 , ring tension [11, 14] moves the sulfur atoms away from the imide oxygens, breaking the 1,5 O‐S chalcogen bonds (Figure 3 a). Interestingly, the O−S distances (3.2 Å) remained below the sum of the vdW radii (3.3 Å), but bond angles (144°) were far from ideal (180°), and the absence of bond path and critical point excluded the presence of a chalcogen bond [19] .…”