Tethered silacrown ethers and ion channeling applications thereof

#The functional behavior of transmembrane ion channels is associated with a broad spectrum of disease states denoted channelopathies. Channelopathies are associated with dysfunction of the ion channels and the proteins that interact with them. Deviations in ion selectivity, gating, conductance, and signal transduction of the channels affect cardiac, renal, synaptic and skeletal muscle organ systems. For example, there are multiple examples of cardiac channelopathies (Schreiber Pharmacology of Potassium Channels, Handbook of Experimental Pharmacology 267, https://doi.org/10.1007/164_2021_513). Within cardiac channelopathies, a particularly intractable class of heart failure is associated with preserved ejection failure (HFpef) which is often associated with sodium-glucose channel dysfunction (McHugh; J of the American College of Cardiology 73(5), 602-611 (2019)). Various motifs of artificial transmembrane ion transporters have demonstrated potential as antibacterial agents. Ions of greatest interest are sodium, potassium, calcium, and chloride. Additionally, zinc and copper are associated with ion channels. The concept of an ion transporter is associated with shuttling an ion across a membrane whereas ion channels are scaffolds that mediate transport across the membrane without significant movements associated with their own translocation.

#Crown ethers are cyclic ether compounds consisting of oxygen atoms each separated by two carbon atoms, which may also be described as cyclic oligomers of ethylene oxide with repeat unit —CH2CH2O—. Crown ethers are named as “X-crown-Y,” where X is the total number of atoms in the ring and Y is the total number of oxygen atoms. Silacrown ethers contain a silicon atom in the ring between two oxygen atoms, replacing one “CH2CH2” unit. In other words, silacrown ethers contain repeating ethylenoxy (CH2CH2O) groups in which one of the ethylene CH2CH2 groups is substituted (replaced) by a silicon atom. Azasilacrown ethers are analogous to silacrown ethers except that a ring oxygen is substituted by a nitrogen atom.

#Aspects of the disclosure relate to a silacrown ether having eleven to about twenty-seven ring atoms of which one of the ring atoms is silicon, wherein the silacrown ether contains one alkyl group on the silicon atom and at least one exocyclic substituent on the silicon ring atom and/or on a carbon ring atom, and wherein the at least one substituent is selected from the group consisting of a substituted or unsubstituted, linear, branched, or cyclic, unsaturated hydrocarbon group having about three to about twenty-four carbon atoms, a peptide, and a peptoid.

#Aspects of the disclosure relate to forming ion channels by creating structures in which the channel can assemble with or without association with an existing natural protein ion channel. Synthetic ion channel molecules often carry central macrocyclic units that are derivatives of crown ethers since the cavity size of these moieties can be adjusted to match the ions of interest, as noted for example, by Takagi (Pure & Appl. Chem., 61(9), 1605 (1989)). On the other hand, structures containing crown ethers are associated with high levels of toxicity, both as ion transporters and channel structures, which is likely associated with the highly stable crown ethers creating a continuous un-gated ion flux. This disclosure incorporates silacrowns which have controlled hydrolytic stabilities into ion channels (as opposed to ion transporters).

#In one aspect of the disclosure, provided is a silacrown ether having eleven to about twenty-seven ring atoms of which one of the ring atoms is silicon, wherein the silacrown ether contains one alkyl group on the silicon atom and at least one exocyclic substituent on the silicon ring atom and/or on a carbon ring atom, and wherein the at least one substituent is selected from the group consisting of a substituted or unsubstituted, unsaturated, linear, branched, or cyclic hydrocarbon group having about three to about twenty-four carbon atoms, a peptide, and a peptoid.

#The silacrown ethers described herein contain eleven to about twenty-seven ring atoms, of which one of the ring atoms is silicon. It may be understood that the non-silicon ring atoms are carbon atoms and oxygen atoms as repeating ethylenoxy (CH2CH2O) groups, and that the ring atoms are non-aromatic. Preferably, the ring contains about fourteen to twenty-seven ring atoms, or about fourteen to about twenty ring atoms, such as fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty ring atoms, most preferably fourteen, seventeen, or twenty ring atoms. The smallest ring, having eleven ring atoms, may be referred to as a sila-11-crown-4 ring structure or, alternatively, a 3,6,9,11-tetraoxa-1-silaundecane nucleus. Other exemplary skeletons include, without limitation, sila-14-crown-5 and sila-20-crown-7.