Activated polyoxazolines and conjugates and compositions comprising the same
The present disclosure provides POZ derivatives having a range of active functional groups allowing conjugation of 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 POZ derivatives and hydrolytically stable target molecule-POZ conjugates created using the disclosed terminally activated monofunctional POZ derivatives. In one embodiment, the POZ derivative is a terminally activated monofunctional POZ derivative.
1. A terminally activated polyoxazoline (POZ) compound of the general structure R 1 -POZ-P p -Q q -W w -U u -X,
wherein
POZ is [N(COR 7 )CH 2 CH 2 ] n
X is an active functional group;
P is —O—;
q is 0;
p, u and w are each 1;
U is a linking group selected from the group consisting of: —(R 16 ) o —, —(CR 5 R 6 ) o —, —NH—R 21 —NHCO—R 22 —;
W is —NH—CO;
R 7 is independently selected for each repeating unit of POZ from an unsubstituted or substituted alkyl, alkenyl or aralkyl group;
R 1 , R 5 -R 6 and R 21 -R 22 are each independently selected from hydrogen, unsubstituted or substituted alkyl, alkenyl or aralkyl group;
R 16 is an unsubstituted alkyl, alkenyl or aralkyl group;
n is an integer from 3 to 1000; and
o is an integer from 1 to 10.
2. The terminally activated POZ compound of claim 1 , wherein the active functional group is protected.
3. The terminally activated POZ compound of claim 1 , wherein R 7 is an unsubstituted or substituted alkyl, alkenyl having from 1 to 12 carbon atoms.
4. The terminally activated POZ compound of claim 1 , wherein R 7 is methyl, ethyl or n-propyl.
5. The terminally activated POZ compound of claim 1 , wherein the active functional group is selected from the group consisting of: aldehyde, active carbonate (O—CO—Z), maleimide, sulfonate ester (OSO 2 —R 23 ), hydrazide, epoxide, iodoacetamide, alkyne, azide, isocyanate, cyanate isothiocyanate, thiocyanate, nitrile, a carbonyldiimidazole derivative, vinylsulfone, carboxylic acid halide, active ester (—CO—Z) and carboxylic acid, 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. The terminally activated POZ compound of claim 5 , wherein the sulfonate ester is tresylate or mesylate.
7. The terminally activated POZ compound of claim 5 , wherein Z is N-succinimidyloxy, chlorine, bromine, sulfo-N-succinimidyloxy, p-nitrophenoxy, 1-imidazolyl, or 1-benzotriazolyloxy.
8. The terminally activated POZ compound of claim 5 , wherein the active functional group is a substituted or unsubstituted piperazinyl or a substituted piperidinyl group.
9. The terminally activated POZ compound of claim 1 , wherein the POZ polymer has a polydispersity value of less than or equal to 1.05.
10. The terminally activated POZ of claim 1 linked to a target molecule.
11. The terminally activated POZ compound of claim 1 , wherein the active functional group forms a linkage with a target molecule and wherein all linkages between the target molecule and the POZ compound are hydrolytically stable in a biological system.
12. A compound having a structure:
(a) CH 3 —[N(COCH 2 CH 3 )CH 2 CH 2 ] n —OCONH—CH 2 CH 2 —NH 2 ; or
(b) CH 3 —[N(COCH 2 CH 3 )CH 2 CH 2 ] n —OCONH—CH 2 —CHO
wherein, n is an integer from 3 to 1000.