Activated polyoxazolines and compositions comprising the same
The present disclosure provides terminally activated monofunctional POZ derivatives having a range of functional active groups allowing conjugation of the monofunctional POZ derivatives to a variety of target molecules under a wide range of reaction conditions to produce a hydrolytically stable target molecule-POZ conjugate. Furthermore, the present disclosure provides novel methods of synthesis for the disclosed terminally activated monofunctional POZ derivatives and hydrolytically stable target molecule-POZ conjugates created using the disclosed terminally activated monofunctional POZ derivatives.
1. A terminally activated polyoxazoline compound having the general structure R 1 —[N(COR 7 )CH 2 CH 2 ] n —S-Q q -X,
wherein
X is an active functional group capable of forming a hydrolytically stable linkage with a target molecule to form a target molecule-POZ conjugate wherein all the linkages between the target molecule and the POZ compound are hydrolytically stable in a biological system;
Q is an optional linking group;
R 1 , and is hydrogen or an unsubstituted or substituted alkyl, alkenyl or aralkyl group;
R 7 is independently selected for each repeating unit from an unsubstituted or substituted alkyl, alkenyl or aralkyl group;
n is an integer from 3 to 1000; and
q is zero or one.
2. The compound of claim 1 where the active functional group is protected.
3. The compound of claim 1 where R 7 has from 1 to 12 carbon atoms.
4. The compound of claim 1 where R 7 is methyl, ethyl or n-propyl.
5. The compounds of claim 1 where the active functional group is selected from the group consisting of aldehydes, active carbonates (—O—CO—Z), maleimides, sulfonate esters (OSO 2 —R 23 ), hydrazide, epoxides, iodoacetamides, alkynes, azides, isocyanates, cyanates isothiocyanates, thiocyanates, nitriles, carbonyldiimidazole derivatives, vinylsulfones, carboxylic acid halides, active esters (—CO—Z) and carboxylic acids, wherein any of the foregoing may be substituted or unsubstituted, Z is an activating group and R 23 is an unsubstituted or substituted alkyl, alkenyl, alkynyl, aralkyl or aryl group.
6. A target molecule POZ conjugate of the general formula A-B-TM, wherein
A is a terminated POZ compound of claim 1 , minus any leaving groups eliminated during the reaction of the active functional group on the POZ compound with a binding partner on a target molecule;
TM is the target molecule, said target molecule containing the binding partner; and
B is a linkage that is hydrolytically stable in a biological system that is formed between the active functional group and the binding partner.
7. The conjugate of claim 6 wherein the active functional group is a maleimide, the binding partner is SH and B is a thioether linkage.
8. The conjugate of claim 6 wherein the active functional group is an active carbonate, the binding partner is NH 2 and B is a urethane linkage.
9. The conjugate of claim 6 wherein the active functional group is an active ester, the binding partner is NH 2 and B is an amide linkage.
10. The conjugate of claim 6 wherein the active functional group is an aldehyde, the binding partner is NH 2 and B is an amine linkage.
11. A method of synthesizing terminally activated polyoxazoline (POZ) compound, said method comprising the steps of:
(a) initiating POZ polymerization to form a POZ polymer with a positive cation on the terminating end; and
(b) terminating said POZ polymer with a mercaptide.
12. The method of claim 11 where the mercaptides comprises the structure R 25 S-D d -X wherein
X is an active functional group or a group capable of being converted to an active functional group, the active functional group capable of forming a hydrolytically stable linkage with a target molecule to form a target molecule-POZ conjugate;
R 25 is a metal;
D is a linking group; and
d is 0 or 1.
13. The method of claim 12 where R 25 is Li, Na or K.
14. The terminally activated polyoxazoline compound of claim 1 having the structure:
(b) CH 3 —[N(COCH 2 CH 3 )CH 2 CH 2 ] n —S—CH 2 CH 2 —CO 2 H
(c) CH 3 —[N(COCH 2 CH 3 )CH 2 CH 2 ] n —S—CH 2 —CO 2 H
(d) CH 3 —[N(COCH 2 CH 3 )CH 2 CH 2 ] n S—CH 2 CH 2 —NH 2
(f) CH 3 —[N(COCH 2 CH 2 CH 3 )CH 2 CH 2 ] n —S—CH 2 CH 2 —CO 2 H
(g) H—[N(COCH 2 CH 3 )CH 2 CH 2 ] n —S—CH 2 CH 2 —CO 2 H
15. The compound of claim 1 , wherein the linking group Q is an unsubstituted or substituted alkyl, alkenyl, aralkyl, heterocyclyl or aryl group, —(CH 2 ) m —CONH—(CH 2 ) m —, —NH—(CH 2 ) m —NHCO—(CH 2 ) m —, —CO—(CH 2 ) m —, —CO—C 6 H 4 —, or —CO—R 8 , —(R 15 ) m — or —(CR 3 R 4 ) m —, wherein m is independently an integer from 1 to 10, R 3 , R 4 , R 11 and R 15 are each independently selected from hydrogen or an unsubstituted or substituted alkyl, alkenyl or aralkyl group and R 8 is —C 6 H 10 —CH 2 —.
16. The compound of claim 1 wherein the POZ polymer has a polydispersity value of less than or equal to 1.20.
17. The method of claim 12 wherein the linking group D is an unsubstituted or substituted alkyl, alkenyl, heterocyclyl or aryl group.