IONIC POLYMERS COMPRISING BIOLOGICALLY ACTIVE COMPOUNDS
Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I): or a stereoisomer, tautomer or salt thereof, wherein R 1 , R 2 , R 3 , L, L 1 , L 2 , L 3 , L 4 , M and n are as defined herein. Methods associated with preparation and use of such compounds are also provided.
1 . A compound having the following structure (I):
or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein:
M is, at each occurrence, independently either:
(i) a biologically active moiety selected from a nonsteroidal anti-inflammatory drug (NSAID), a kinase inhibitor, an anthracycline, an epidermal growth factor receptor (EGFR) inhibitor, an alkylating agent, and an anti-cancer drug, or
(ii) a fluorescent dye,
wherein at least one occurrence of M is the biologically active moiety;
L is a physiologically cleavable linker;
L 1 , L 2 and L 3 are, at each occurrence, independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatomic linker;
L 4 is, at each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene or heteroalkynylene linker comprising one or more charged moieties, provided at least one charged moiety is not a phosphate ester;
R 1 is, at each occurrence, independently H, alkyl or alkoxy;
R 2 and R 3 are each independently —H, —OH, —SH, alkyl, alkoxy, alkylether, heteroalkyl, alkylaminyl, alkylcarbonyl, alkoxycarbonyl, —OP(═R a )(R b )R c , Q or a protected form thereof, or L′;
R a is O or S;
R b is OH, SH, O − , S − , OR d or SR d ;
R c is OH, SH, O − , S − , OR d , OL′, SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkylether, alkoxyalkylether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether;
R d is a counter ion;
Q is, at each occurrence, independently a moiety comprising a reactive group, or protected form thereof, capable of forming a covalent bond with a complementary reactive group Q′ on a targeting moiety;
L′ is, at each occurrence, independently a targeting moiety, a solid support, solid support residue, or a linker comprising a covalent bond to a targeting moiety, Q, solid support, solid support residue or a further compound of structure (I); and
n is an integer of one or greater.
2 . The compound of claim 1 , wherein the charged moieties are positively charged.
3 . The compound of claim 1 , wherein the charged moieties are negatively charged.
4 . The compound of claim 1 , wherein L 4 comprises one of the following structures:
wherein:
R is, at each occurrence, independently H or C 1 -C 6 alkyl;
x is an integer from 0 to 6; and
m is an integer of 1 or greater.
5 . The compound of claim 1 , wherein L is at each occurrence a linker comprising a functional group capable of formation by reaction of two complementary reactive groups.
6 . The compound of claim 1 , wherein L is, at each occurrence, independently a linker comprising an amide bond, an ester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a ketone, a diol, a cyano, a nitro, a heterocycle, a heteroaryl or combinations thereof.
7 . The compound of claim 1 , wherein R 2 and R 3 are each independently —OH or —OP(═R a )(R b )R c .
8 . The compound of claim 1 , wherein one of R 2 or R 3 is —OH or —OP(═R a )(R b )R c , and the other of R 2 or R 3 is Q or a linker comprising a covalent bond to Q.
9 . The compound of claim 1 , wherein Q comprises a sulfhydryl, disulfide, N-succinimide ester, imidoester, polyflourophenyl ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acid halide, sulfonyl halide, phosphine, α-haloamide, biotin, amino or maleimide functional group.
10 . The compound of claim 1 , wherein Q has one of the following structures:
wherein:
X is halo; and
EWG is an electron withdrawing group.
11 . The compound of claim 1 , wherein one of R 2 or R 3 is L′, and L′ is a targeting moiety or a linker to a targeting moiety.
12 . The compound of claim 11 , wherein L′ is a linker to a targeting moiety, the linker comprising a heteroalkylene linker.
13 . The compound of claim 1 , wherein n is an integer from 1 to 100.
14 . The compound of claim 1 , wherein the targeting moiety is an antibody specific for a tumor cell antigen.
15 . The compound of claim 1 , wherein the compound has one of the following structures:
wherein:
x is an integer of 1 or greater, and
y is an integer of 2 or greater.
16 . A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
17 . A composition comprising a plurality of conjugates, the conjugates comprising a compound of claim 1 comprising a covalent bond to an antibody via a single linkage, wherein the plurality of conjugates has at least 90% structural homogeneity.
18 . The composition of claim 16 , wherein one of R 2 and R 3 is —OP(═R a )(R b ) OL′ or L′, and L′ is the targeting moiety or a linker comprising a covalent bond to the targeting moiety, and wherein the targeting moiety is an antibody.
19 . The compound of claim 1 , wherein the one or more charged moieties, at each occurrence, independently comprise a protonated amine, a quaternary amine, a carboxylic acid, or a sulfate functional group.
20 . The compound of claim 1 , wherein the one or more charged moieties, at each occurrence, independently are within a backbone of the compound or covalently bound pendant to the backbone via an optional linker.
21 . The compound of claim 1 , wherein M is not the same at each occurrence and wherein each M is selected to have the same, similar, or different therapeutic properties from each other.
22 . The compound of claim 5 , wherein the functional group is the product of a click reaction.