Hydrophilic self-immolative linkers and conjugates thereof
The present disclosure provides compounds with a hydrophilic self-immolative linker, which is cleavable under appropriate conditions and incorporates a hydrophilic group to provide better solubility of the compound. The compounds of the present disclosure comprise a drug moiety, a targeting moiety capable of targeting a selected cell population, and a linker which contains an acyl unit, an optional spacer unit for providing distance between the drug moiety and the targeting moiety, a peptide linker which can be cleavable under appropriate conditions, a hydrophilic self-immolative linker, and an optional second self-immolative spacer or cyclization self-elimination linker.
1. A compound of the formula (II):
or a salt or solvate or stereoisomer thereof;
wherein:
D is a drug moiety;
T is a targeting moiety;
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit.
2. The compound of claim 1 , wherein L 1 is a bond.
3. The compound of claim 1 , wherein L 1 is a second self-immolative linker or a cyclization self-elimination linker.
4. The compound of claim 3 , wherein L 1 is an aminobenzyloxycarbonyl linker.
5. The compound of claim 3 , wherein L 1 is selected from the group consisting of
6. The compound of claim 3 , wherein L 1 is selected from the group consisting of
7. The compound of claim 1 , wherein L 2 is a bond.
8. The compound of claim 2 , wherein L 2 is a second self-immolative linker.
9. The compound of claim 8 , wherein L 2 is an aminobenzyloxycarbonyl linker.
10. The compound of claim 8 , wherein L 2 is selected from
11. The compound of claim 1 , wherein L 3 is a peptide linker of 1 to 10 amino acid residues.
12. The compound of claim 11 , wherein L 3 is a peptide linker of 2 to 4 amino acid residues.
13. The compound of claim 1 , wherein L 3 is a peptide linker comprising at least one lysine or arginine residue.
14. The compound of claim 1 , wherein L 3 is a peptide linker comprising an amino acid residue selected from lysine, D-lysine, citrulline, arginine, proline, histidine, ornithine and glutamine.
15. The compound of claim 1 , wherein L 3 is a peptide linker comprising an amino acid residue selected from valine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine.
16. The compound of claim 11 , wherein L 3 is a dipeptide unit selected from valine-citrulline, proline-lysine, methionine-D-lysine, asparagine-D-lysine, isoleucine-proline, phenylalanine- lysine, and valine-lysine.
17. The compound of claim 16 , wherein L 3 is valine-citrulline.
18. The compound of claim 1 , wherein L 4 is a bond.
19. The compound of claim 1 , wherein L 4 is a spacer.
20. The compound of claim 19 , wherein the spacer is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.
21. The compound of claim 19 , wherein L 4 is L 4a -C(O), L 4a -C(O)—NH, L 4a -S(O) 2 , or L 4a -S(O) 2 —NH, wherein each L 4a is independently polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.
22. The compound of claim 19 , wherein L 4 is L 4a -C(O), wherein L 4a is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.
23. The compound of claim 19 , wherein L 4 is L 4a -C(O), wherein L 4a is a polyalkylene glycol.
24. The compound of claim 19 , wherein L 4 is L 4a -C(O), wherein L 4a is a polyethylene glycol.
25. The compound of claim 19 , wherein the spacer is of the formula —CH 2 —(CH 2 —O—CH 2 ) m —CH 2 —C(O)—, wherein m is an integer from 0 to 30.
26. The compound of claim 19 , wherein L 4 is L 4a -C(O), wherein L 4a is alkylene.
27. The compound of claim 1 , wherein A is selected from the group consisting of
wherein each Q 2 is NH or O, and each q is independently an integer from 1 to 10.
28. The compound of claim 27 , wherein A is selected from the group consisting of
wherein each Q 2 is independently NH or O and each q is independently an integer from 1 to 10.
29. The compound of claim 28 , wherein q is 2, 3, 4, or 5.
30. The compound of claim 1 , wherein A is selected from the group consisting of
wherein each Q 2 is independently NH or O.
31. The compound of claim 1 , wherein T is an antibody.
32. The compound of claim 31 , wherein T is h5F1Ca.1 or c5D7.
33. The compound of claim 1 , wherein D is an amino-containing drug moiety, wherein the drug is connected to L 1 or X through the amino group.
34. The compound of claim 33 , wherein D is duocarmycin, dolastatin, tubulysin, doxorubicin (DOX), paclitaxel, or mitomycin C (MMC), or an amino derivative thereof.
35. The compound of claim 33 , wherein D is an amino derivative of duocarmycin selected from the group consisting of
36. The compound of claim 33 , wherein D is dolastatin:
37. The compound of claim 1 , wherein -A-L 4 -L 3 -L 2 - is
38. The compound of claim 1 , wherein
moiety is:
39. The compound of claim 1 , wherein
moiety is:
40. The compound of claim 1 , wherein
moiety is:
41. A pharmaceutical composition comprising a compound of claim 1 , or a salt or solvate or stereoisomer thereof; and a pharmaceutically acceptable carrier.
42. A method of killing a cell, comprising administering to the cell an amount of the compound of claim 1 , or a salt or solvate or stereoisomer thereof, sufficient to kill the cell.
43. The method of claim 42 , wherein the cell is a cancer cell.
44. The method of claim 43 , wherein the cancer cell is a gastric cancer cell, pancreatic cancer cell, colorectal cancer cell, lung cancer cell, lymphoma cell, breast cancer cell, cervical cancer cell or ovarian cancer cell.
45. A method of treating cancer in an individual in need thereof comprising administering to the individual an effective amount of a compound of claim 1 , or a salt or solvate or stereoisomer thereof.
46. The method of claim 45 , wherein the cancer is gastric cancer, pancreatic cancer, colorectal cancer, lung cancer, lymphoma, breast cancer, cervical cancer or ovarian cancer.
47. A kit comprising a compound of claim 1 , or a salt or solvate or stereoisomer thereof.
48. The kit of claim 47 , further comprising instructions for use in the treatment of cancer.
49. A compound of Formula (XII)
or a salt or solvate or stereoisomer thereof; wherein R is NO 2 or NH 2 .
50. A method of preparing Compound X:
or a salt or solvate or stereoisomer thereof;
wherein:
L 2 is a bond or a second self-immolative linker;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit; and
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
comprising reacting Compound W: A-L 4 -L 3 -L 2 ; and Compound I:
51. A method of preparing Compound Z:
or a salt or solvate or stereoisomer thereof;
wherein:
D is a drug moiety;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
comprising: reacting Compound X:
and p-nitrophenyl chloroformate to form Compound Y:
reacting Compound Y with a compound comprising L 1 -D.
52. A method of preparing Compound X 1 :
or a salt or solvate or stereoisomer thereof;
wherein:
L 2 is a bond or a second self-immolative linker;
L 3 is a peptide linker; and
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
comprising: reacting Compound W 1 : L 3 -L 2 ; and Compound I:
53. A method of preparing Compound Y 1 :
or a salt or solvate or stereoisomer thereof;
wherein:
D is a drug moiety;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker; and
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
comprising: reacting Compound X 1 :
and a compound comprising L 1 -D.
54. A method of preparing Compound Z:
or a salt or solvate or stereoisomer thereof;
wherein:
D is a drug moiety;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer;
A is an acyl unit; and
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
comprising: reacting Compound Y 1 :
and a compound comprising A-L 4 .
55. A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
L 2 is a bond or a second self-immolative linker;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit; and
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl.
56. A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
D is a drug moiety;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is bond or a spacer; and
A is an acyl unit; and
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl.
57. A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
L 2 is a bond or a second self-immolative linker;
L 3 is a peptide linker; and
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl.
58. A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
D is a drug moiety;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker; and
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl.
59. The method of claim 53 , wherein Compound X 1 is reacted with p-nitrophenyl chloroformate to form an activated carbonate; and the activated carbonate is reacted with the compound comprising L 1 -D.