Isolatable, water soluble, and hydrolytically stable active sulfones of poly(ethylene glycol) and related polymers for modification of surfaces and molecules
View Patent ↗Water soluble activated polymers are provided containing an active ethyl sulfone moiety having a reactive site located at the second carbon from the sulfone group. In an embodiment, a poly(ethylene glycol) (PEG) derivative is disclosed that is activated with the active ethyl sulfone moiety for selective attachment to thiol moieties on molecules and surfaces. The activated PEG is water soluble, hydrolytically stable for extended periods, and forms hydrolytically stable linkages with thiol moieties. The linkages generally are not reversible in reducing environments. The PEG derivative is useful for modifying the characteristics of substances including modifying biologically active molecules and surfaces for biocompatibility.
1. A method for synthesizing a water soluble activated organic polymer having an active ethyl sulfone moiety wherein the linkage between the polymer and the active ethyl sulfone moiety is stable against hydrolysis, the method comprising the steps of covalently linking a sulfur containing moiety directly to a terminal carbon atom of the polymer and then converting the sulfur containing moiety to an active ethyl sulfone moiety having a reactive site located at the second carbon from the sulfone group, wherein said polymer is selected from the group consisting of poly(alkylene oxides), poly(oxyethylated polyols) and poly(olefinic alcohols).
2. The method of claim 1 , further comprising the step of isolating the activated polymer having the active ethyl sulfone moiety.
3. The method of claim 1 , wherein said step of linking a sulfur containing moiety directly to a terminal carbon atom of the polymer comprises the steps of activating at least one activatable hydroxyl moiety on the polymer and reacting the activated hydroxyl moiety with a compound comprising a thiol group covalently attached to an ethyl group to cause a sulfur atom to be covalently linked directly to the terminal carbon of the polymer.
4. The method of claim 3 , wherein said step of activating at least one activatable hydroxyl moiety comprises hydroxyl substitution or replacement of the hydroxyl hydrogen with a more reactive moiety.
5. The method of claim 4 , wherein said step of activating at least one activatable hydroxyl moiety comprises replacing the hydroxyl group with a halide.
6. The method of claim 4 , wherein said step of activating at least one activatable hydroxyl moiety comprises reacting the hydroxyl moiety with an acid or acid derivative to form a reactive ester.
7. The method of claim 6 , wherein the reactive ester is selected form the group consisting of sulfonate esters, carboxylate esters, and phosphate esters.
8. The method of claim 6 , wherein the acid or acid derivative is a sulfonyl acid halide selected from the group consisting of methanesulfonyl chloride and p-toluenesulfonyl chloride.
9. The method of claim 3 , wherein said reacting step comprises reacting the activated hydroxyl moiety with mercaptoethanol.
10. The method of claim 1 , wherein said converting step comprises oxidizing the sulfur atom to form an ethyl sulfone.
11. The method of claim 10 , wherein said oxidizing step comprises oxidizing the sulfur atom with an oxidizing agent selected from the group consisting of sodium perborate and hydrogen peroxide.
12. The method of claim 10 , wherein said converting step further comprises attaching a reactive group to the terminus of the ethyl sulfone moiety, thereby forming the active ethyl sulfone.
13. The method of claim 12 , wherein said ethyl sulfone comprises a terminal activatable hydroxyl group and said step of attaching a reactive group to the terminus of the ethyl sulfone moiety comprises activating the terminal activatable hydroxyl moiety by hydroxyl substitution or replacement of the hydroxyl hydrogen with a more reactive moiety.
14. The method of claim 1 , wherein the polymer is poly(ethylene glycol).
15. The method of claim 1 , wherein the polymer is a poly(ethylene glycol) molecule having at least one activatable hydroxyl group, and wherein said linking step comprises (a) activating the at least one activatable hydroxyl group by substituting the hydroxyl group with a halide or replacing the hydroxyl hydrogen with an ester group to form an ester or halide substituted poly(ethylene glycol) molecule, and (b) reacting the ester or halide substituted poly(ethylene glycol) molecule with mercaptoethanol to substitute the mercaptoethanol radical for the ester or halide moiety; and further wherein said converting step comprises (c) reacting the mercaptoethanol substituted poly(ethylene glycol) molecule with an oxidizing agent to oxidize sulfur in the mercaptoethanol moiety to form an ethyl sulfone moiety and (d) converting the terminal hydroxyl group of the ethyl sulfone moiety to an ester or halide moiety to form the active ethyl sulfone.
16. The method according to claim 15 , further comprising reacting the active ethyl sulfone moiety of the polymer with a thiol-containing surface or biologically active molecule.
17. The method according to claim 16 , wherein the active ethyl sulfone moiety of the polymer is reacted with a thiol-containing protein or fragment thereof.
18. The method according to claim 1 , further comprising reacting the active ethyl sulfone moiety of the polymer with a thiol-containing surface or biologically active molecule.
19. The method according to claim 18 , wherein the active ethyl sulfone moiety of the polymer is reacted with a thiol-containing protein or fragment thereof.
20. The method according to claim 1 , wherein the polymer comprising the active ethyl sulfone moiety is a homobifunctional polymer or a heterobifunctional polymer.