Cross-linking compounds and methods of use thereof
Compounds comprising a cross-linking moiety and a protecting group are described herein along with their methods of use. The cross-linking moiety may comprise an indoxyl and the protecting group may comprise a sugar (e.g., a glucuronide or glucoside), phosphoester, or sulfoester group. The cross-linking moiety and protecting group may be attached to each other via an oxygen atom, sulfur atom, or linker. In some embodiments, the linker attaching the cross-linking moiety and protecting group is a self-immolative linker. A compound of the present invention may cross-link under physiological conditions and/or in vivo.
1 . A compound having a structure of Formula I:
wherein:
Z is each independently a hydroxyl, amino, enzyme, polyiodide binding matrix, a targeting agent, a circulation enhancing agent, water solubilizing group, chromophore, or bioconjugatable group;
L is a linker that comprises a polyethylene glycol;
X 1 is absent, —O—, or —S—;
each R 1 is independently selected from a halogen, alkyl, alkenyl, alkynyl, —OH, alkoxy, acyloxy, carboxy, carboxylic ester, boronate ester, thioalkoxy, and amino;
each R 2 is independently —CH 2 OH or —C(O)OH;
each X 2 is independently —O—, —S—, or a self-immolative linker;
p is an integer of 1 to 6;
b is an integer of 1 to 6; and
each n is independently an integer of 1 to 4;
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein R 2 is —CH 2 OH.
3 . The compound of claim 1 , wherein R 2 is —C(O)OH.
4 . The compound of claim 1 , wherein the compound has a structure of Formula I and Z, L, X 1 , R 1 , R 2 , X 2 , p, b, and n are each as defined above.
5 . The compound of claim 1 , wherein X 2 is O.
6 . The compound of claim 1 , wherein X 2 is a self-immolative linker.
7 . The compound of claim 1 , wherein L has a structure of Formula IV:
wherein:
each Q is independently absent or is —(CH 2 ) q —, alkenyl, alkynyl, aryl, —C(O)—, or —CH 2 C(O)— each of which may be substituted or unsubstituted, where q is an integer of 2 to 5, 10, or 20;
each m is independently an integer of 1 to 100; and
R 3 is a hydrogen, Z as defined above, a moiety having a structure of Formula I as defined above, or an aryl or heterocycle each of which may be substituted or unsubstituted.
8 . The compound of claim 1 , wherein L comprises:
wherein R 3 is Z as defined above, a moiety having a structure of Formula I as defined above, or an aryl, alkylamino, alkoxy, or heterocycle, each of which may be substituted or unsubstituted.
9 . The compound of claim 8 , wherein R 3 has a structure of:
wherein each R 4 is independently a hydrogen or is a substituted or unsubstituted alkyl, alkenyl, or alkynyl.
10 . The compound of claim 8 , wherein R 3 has a structure of:
wherein each R 5 is independently a hydrogen or is a substituted or unsubstituted alkyl, alkenyl, or alkynyl.
11 . The compound of claim 1 , wherein Z has a structure of:
12 . The compound of claim 1 , wherein the compound has a structure of Formula I″:
wherein at least one of R 1 in Formula I″ is a halogen; and Z, L, X 1 , R 1 , R 2 , X 2 , p, b, and n are each as defined above.
13 . The compound of claim 12 , wherein both of R 1 in Formula I″ is a halogen.
14 . The compound of claim 12 , wherein X 2 and/or X 1 is O.
15 . The compound of claim 1 , wherein the compound has the following structure: