Heterocyclic-dithiol click chemistry
Inventors
Assignees
Northeastern University Boston
Publication Number
US-12171854-B2
Publication Date
2024-12-24
Expiration Date
2038-07-11
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Abstract
Disclosed are polymers, methods of making polymers, and compositions, focused on cross-linking heterocycles comprising a moiety of Formula I with thiols and thiolates.
Core Innovation
The invention provides polymers, methods of making polymers, and compositions focused on cross-linking heterocycles containing a moiety of Formula I with thiols and thiolates. The central method involves covalent coupling of molecules by providing first molecules comprising a moiety of Formula I, where W is independently S or Se, Y is independently S, Se, S(O), Se(O), S(O)2, or Se(O)2, and X with W and Y forms a substituted or unsubstituted 3–10-membered heterocyclic ring, and contacting them with second molecules having at least one thiol functional group to form covalent bonds between the S or Se atoms and the free thiol groups.
The problem addressed is the need for a biocompatible replacement for dienes in dithiolate-diene reactions and for chemical tools with improved selectivity for cross-linking thiols. Prior art thiol-ene cross-linkers lack cross-linking selectivity and cause terminal dead-end modifications, resulting in toxicity and limiting in vivo applications. Existing methods are not selective for cross-linking thiols and cause toxicity by modifying essential cysteines or generating adverse immune responses.
This invention introduces a biocompatible and selective chemistry for cross-linking thiols using heterocycles with a moiety of Formula I (such as cyclic disulfides or cyclic thiosulfinates), avoiding dead-end modifications and providing high reaction yields, stereospecificity, and reaction rates consistent with click chemistry. The methods can produce polymers, dendrimers, and functional coatings by leveraging the selective covalent coupling between specific heterocyclic moieties and thiol functional groups, applicable to a broad class of biomolecules and materials.
Claims Coverage
The patent claims cover two main inventive features based on the independent claims relating to polymers derived using specific cross-linkers and methods of preparing such polymers.
Polymer derived from a first monomer and a first cross-linker containing Formula I moiety
The polymer is created from: - A first monomer that has at least two thiol functional groups. - A first cross-linker that comprises a moiety of Formula I: - W is independently S or Se. - Y is independently S, Se, S(O), Se(O), S(O)2, or Se(O)2. - X together with W and Y forms a substituted or unsubstituted 3–10-membered heterocyclic ring. This feature enables formation of polymers through covalent bonds between the S or Se atoms of such cross-linkers and the thiol groups of the monomers.
Method of preparing the polymer via cross-linking using Formula I moiety
The method involves: 1. Providing a plurality of first monomers with at least two thiol functional groups. 2. Contacting them with a plurality of first cross-linkers, each comprising a moiety of Formula I as above. 3. Conducting the reaction under conditions suitable for covalent bond formation between the thiol groups and the cross-linker, resulting in the polymer through covalent cross-linking via these cross-linkers.
In summary, the inventive features comprise both a polymer structure and a method of polymer preparation utilizing a heterocyclic cross-linker of defined Formula I to achieve selective thiol cross-linking.
Stated Advantages
The moieties of Formula I are more biocompatible than dienes or other commonly used electrophiles for cross-linking thiols.
The methods proceed in high yield, with stereoselectivity, and at a high reaction rate driven by thermodynamic driving force, consistent with click chemistry.
Binding to single thiolates is reversible whereas dithiol cross-linking is not, and the leaving group is only expended upon cross-linking, reducing dead-end modifications.
Once a disulfide bond is formed to the first thiol moiety, the effective concentration of the second thiol moiety increases, enhancing cross-linking efficiency.
Cross-linking is driven by the considerable bond enthalpies of S—S, S—Se, or Se—Se bond and water formation, ensuring high yields and reliable results.
Other reactive functional groups, including carboxylates, amines, and disulfides, are avoided, leading to orthogonality and reduced off-target effects.
Documented Applications
Self-healing polymers can be created using the disclosed methods and polymers.
The invention enables the synthesis of hydrogels and nanogels through selective cross-linking.
Thin films and coatings, including electrochemically active monolayers and multilayers for surfaces and devices, can be formed using the described chemistry.
Functionalization, corrosion prevention, pacifying, and passivation of surfaces are achieved using these methods and polymers.
Synthetic click chemistry applications, including the functionalization of dyes, tags, bifunctional or trifunctional reagents, PEGylation reagents, biomolecules, and substrates.
Photochromic agents and flavorants can be synthesized using the described cross-linking chemistry.
Functionalization of ionic liquids is possible with the invention’s chemical tools.
Creation of self-assembled monolayers and molecular scale electronics.
Production of superconductors using the inventive methods or polymers.
Enhancement of battery capacity retention, including in lithium–sulfur batteries, using cyclic thiosulfinates or related moieties.
Use in cosmetic treatments for keratin-containing materials, such as hair, fingernails, and toenails, via selective cross-linking of thiols.
Pharmacological stabilization of proteins, for example, stabilization of SOD1 and DJ-1 which are implicated in neurodegenerative diseases.
Method for transporting a molecule of interest across a cell membrane by functionalizing it with a moiety of Formula I to reversibly bind to cell membrane transport proteins.
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