Programmable polymeric drugs
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 , M and n are as defined herein. Methods associated with preparation and use of such compounds is also provided.
1. A compound having the following structure (IA):
or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein:
M is, at each occurrence, independently a biologically active moiety selected from an NSAID, a kinase inhibitor, an anthracycline, an EGFR inhibitor, an alkylating agent, and anti-cancer drug; or a fluorescent dye, provided at least one occurrence of M is not a fluorescent dye;
L is a physiologically cleavable linker;
L 2 and L 3 are, at each occurrence, independently absent or an 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;
R 1 is, at each occurrence, independently H, alkyl or alkoxy;
R 2 and R 3 are each independently OH, SH, alkyl, alkoxy, alkylether, heteroalkyl, —OP(═R a )(R b )R c , Q, or a protected form thereof, or L′;
R 4 is, at each occurrence, independently OH, SH, O − , S − , OR d or SR d ;
R 5 is, at each occurrence, independently oxo, thioxo or absent;
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 linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support, a linker comprising a covalent bond to a solid support residue, a linker comprising a covalent bond to a nucleoside or a linker comprising a covalent bond to a further compound of structure (IA);
m is, at each occurrence, independently an integer of zero or greater; and
n is an integer of one or greater.
2. The compound of claim 1 , wherein L 4 is ethylene oxide or polyethylene oxide, and the compound has the following structure (IB):
wherein z is an integer from 1 to 100.
3. The compound of claim 1 , wherein the compound has the following structure (IC):
wherein:
x 1 , x 2 , x 3 and x 4 are, at each occurrence, independently an integer from 0 to 6; and z is an integer from 1 to 100.
4. The compound of claim 1 , wherein the compound has the following structure (ID):
wherein:
x 1 , x 2 , x 3 and x 4 are, at each occurrence, independently an integer from 0 to 6; and y is an integer from 1 to 6.
5. The compound of claim 4 , wherein y is 2, and x 1 , x 2 , x 3 and x 4 are each 1 at each occurrence.
6. The compound of claim 1 , wherein R 4 is, at each occurrence, independently OH, O − or OR d , R 5 is, at each occurrence, oxo, and R 1 is, at each occurrence, H.
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 and R 3 is OH or —OP(═R a )(R b )R c , and the other of R 2 and R 3 is Q or a linker comprising a covalent bond to Q.
9. The compound of claim 1 , wherein one of R 2 and R 3 is —OP(═R a )(R b )R c or L′.
10. The compound of claim 9 , wherein R c is OL′, wherein L′ is a targeting moiety or a linker to a targeting moiety, the linker comprising an alkylene oxide or phosphodiester moiety, or combinations thereof.
11. The compound of claim 10 , wherein L′ has the following structure:
wherein:
m″ and n″ are independently an integer from 1 to 10;
R c is H, an electron pair or a counter ion; and
L″ is the targeting moiety or a linkage to the targeting moiety.
12. The compound of claim 1 , wherein the targeting moiety is an antibody or cell surface receptor antagonist, wherein the antibody or cell surface receptor antagonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate, or a MET inhibitor.
13. The compound of claim 1 , wherein R 2 or R 3 has one of the following structures:
14. 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 or combinations thereof.
15. The compound of claim 1 , wherein M is, at each occurrence, independently an anti-cancer drug, and the targeting moiety is an antibody specific for a tumor cell antigen, wherein the tumor cell antigen is an EGFR, a HER 2, a folate receptor, CD20 or CD 33.
16. The compound of claim 1 , wherein at least one occurrence of M has one of the following structures:
17. The compound of claim 1 , wherein the compound has one of the following structures:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein R 2 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein R 2 has the following structure:
wherein:
z is 3, 4, 5, or 6;
m is 2, 3, 4, or 5; and
n is 1-10;
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
m″ is 4 or 10; and
R 3 has the following structure:
wherein:
R 2 has the following structure:
m″ is 4 or 10; and
R 3 has the following structure:
wherein:
R 2 has the following structure:
m″ is 4 or 10; and
R 3 has the following structure:
wherein:
R 2 has the following structure:
m″ is 4 or 10; and
R 3 has the following structure:
wherein:
R 2 has the following structure:
m″ is 4 or 10; and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein R 2 or R 3 has the following structure:
wherein R 3 has the following structure:
wherein R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein R 3 has the following structure:
wherein R 3 has the following structure:
wherein R 3 has the following structure:
wherein R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein:
R 2 has the following structure:
and
R 3 has the following structure:
wherein R 3 has the following structure:
wherein n is 23;
wherein:
A is an antibody;
F, F′ and F″ have the following structures:
N′ has the following structure:
I′ has the following structure:
D′ has the following structure:
D″ has the following structure:
AF has the following structure:
and
dT has the following structure:
18. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
19. A composition comprising a plurality of conjugates, each of the plurality of conjugates comprising a compound of claim 1 , wherein one of R 2 and R 3 is —OP(═R a )(R b )OL′ or L′, and L′ is an antibody or a linker comprising a covalent bond to the antibody, the antibody covalently bound to two or more biologically active moieties via a single linkage, wherein the single linkage is a linkage to a polymer backbone of the compound of claim 1 , the polymer backbone comprising the two or more biologically active moieties covalently bound thereto.
20. A method of treating a cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , wherein each M is independently an anti-cancer drug effective for treating the cancer.