Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
The present disclosure relates to pyrrolobenzodiazepine dimer prodrugs and ligand-linker conjugates thereof. The present disclosure also relates to compositions and uses of said prodrugs and conjugates.
1. A conjugate of Chemical Formula IIIa, IIIb, or a pharmaceutically acceptable salt thereof:
wherein
a dotted line represents an optional double bond;
ligand is an protein;
R 1 is selected from H, OH, ═O, ═CH 2 , CN, R m , OR m , halo, and dihalo;
R m′ is selected from R m , CO 2 R m , COR m , CHO, CO 2 H, and halo;
R m is selected from optionally substituted C 1-12 alkyl, optionally substituted C 6 aryl, optionally substituted C 6 heteroaryl, and optionally substituted C 3-6 cycloalkyl, wherein the optional substituent is C 1-12 alkyl;
R 2 , R 3 , and R 5 are each independently selected from H, R m , OH, OR m , NH 2 , NHR m , NR m R m′ , NO 2 , and halo;
R 4 is selected from H, R m , OH, OR m , NH 2 , NHR m , NR m R m , NO 2 , halo, C 1-6 alkyl, or C 1-6 alkoxy;
R n , R o , R p , and R q are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, and 5- to 7-membered heteroaryl;
X and X′ are each independently selected from —C(O)O—, —C(O)—, and —C(O)NR—;
Xa and Xa′ are each independently a bond or C 1-6 alkylene;
Y and Y′ are each independently selected from O, S, and N(H);
R 6 is a substituted or unsubstituted saturated or unsaturated C 3-12 hydrocarbon chain, wherein the chain may comprise one or more heteroatoms, NMe, or a substituted or unsubstituted aromatic ring, the chain or aromatic ring may be substituted with —NH, —NR m , —NHC(O)R m , —NHC(O)CH 2 —[OCH 2 CH 2 ] n —R, or —[CH 2 CH 2 O] n —R, wherein
n is 1 to 12;
R 7 is H or C 1-6 alkyl;
Z a and Z b are each independently O, N, or S;
R 12a , R 13a , and R 14a are each independently H, C 1-6 alkyl: or wherein R 13a and R 14a combine with the carbon to which they are attached to form a - to 7-membered heterocyclyl;
R 1 ′, R 2 ′, R 3 ′, R 4 ′, and R 5 ′ are as defined for R 1 , R 2 , R 3 , R 4 , and R 5 , respectively;
G and G′ denote a glucuronide group;
each Z and Z′ is selected from H, C 1-8 alkyl, halo, NO 2 , CN,
R 9 , R 10 , and R 16 are each independently selected from H, C 1-8 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, and methyloxyalkyl;
n is an integer from 1 to 3;
W is —C(O)—, —C(O)NR″—, or —C(O)O—,
R″ is H or C 1-8 alkyl;
L is one or more units selected from a branching unit, a connection unit, and a binding unit or a combination of these units: wherein the connection unit connects W with a binding unit, W with a branching unit, a branching unit with another branching unit, or a branching unit with a binding unit, and the branching unit connects a connection unit with W or the connection unit with another connection unit;
the branching unit is a C 2-100 alkenyl (wherein a carbon atom of the alkenyl may be substituted with one or more heteroatoms selected from the group consisting of N, O, and S and the alkenyl may be further substituted with one or more C 1-20 alkyls), a hydrophilic amino acid, —C(O)—, —C(O)NR″″—, —C(O)O—, —(CH 2 ) s —NHC(O)—(CH 2 ) t —, —(CH 2 ) u —C(O)NH—(CH 2 ) v —, —(CH 2 ) s —NHC(O)—(CH 2 ) t —C(O)—, —(CH 2 ) u —C(O)NH—(CH 2 ) v —C(O)—, —S(O) 2 NR″″—, —P(O)R′″″NR″″—, —S(O)NR″″—, or —PO 2 NR″″—;
R″″ and R′″″ each independently denote H, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl, or C 5-20 aryl;
s, t, u, and v are each independently an integer from 0 to 10;
the connection unit is —(CH 2 ) r (V(CH 2 ) p ) q —;
r is an integer from 0 to 10;
p is an integer from 0 to 12;
q is an integer from 1 to 20;
V denotes a single bond, —O—, or S—;
the binding unit is
and
L 1 is a single bond or C 2-30 alkenyl;
R 11 is H or C 1-10 alkyl; and
L 2 denotes C 2-30 alkenyl.
2. The conjugate of claim 1 , wherein a dotted line represents presence of a double bond between the carbons bearing R 1 and R 7 or R 1′ and R 7′ .
3. The conjugate of claim 1 , wherein:
R 1 is selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 5-7 aryl, and substituted or unsubstituted C 3-6 heteroaryl; R 2 , R 3 , and R 5 are each independently H or OH; and
R 4 is C 1-6 alkoxy.
4. The conjugate of claim 1 , wherein X and X′ are each independently selected from —C(O)O*, —C(O)*, and —C(O)NR*, wherein each R independently is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , halo, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted C 1-8 alkoxy, wherein C 1-8 alkyl or C 1-8 alkoxy may be substituted with OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , or halo.
5. The conjugate of claim 1 , wherein Y and Y′ are each O.
6. The conjugate of claim 1 , wherein R 6 is a substituted or unsubstituted saturated or unsaturated C 3-8 hydrocarbon chain and the chain comprises one or more heteroatoms or a substituted or unsubstituted aromatic ring, wherein the heteroatom is O, S, or N(H) and the aromatic ring is benzene, pyridine, imidazole, or pyrazole, and a hydrogen in the chain or aromatic ring may be replaced with —NHC(O)CH 2 —[OCH 2 CH 2 ] n —R or —[CH 2 CH 2 O] n —R; and n is 1 to 6.
7. The conjugate of claim 1 , wherein
W is —C(O)—, —C(O)NR′″—, or —C(O)O—, wherein R′″ is H or C 1-8 alkyl,
L is one or more units selected from a branching unit, a connection unit, and a binding unit or a combination of these units, wherein the connection unit connects W with a binding unit, W with a branching unit, a branching unit with another branching unit, or a branching unit with a binding unit, and the branching unit connects a connection unit with W or the connection unit with another connection unit;
the branching unit is a C 2-8 alkenyl wherein a carbon atom of the alkenyl may be replaced with one or more heteroatoms selected from N, O, and S and the alkenyl may be further substituted with one or more C 1-6 alkyls, a hydrophilic amino acid, —C(O)—, —C(O)NR″″—, —C(O)O—, —(CH 2 ) s —NHC(O)—(CH 2 ) t —, —(CH 2 ) u —C(O)NH—(CH 2 ) v —, —(CH 2 ) s —NHC(O)—(CH 2 ) t —C(O)—, or —(CH 2 ) u —C(O)NH—(CH 2 ) v —C(O)— (wherein R″″ is H, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl, or C 5-20 aryl and s, t, u, and v are each independently 0 to 5;
the connection unit is —(CH 2 ) r (V(CH 2 ) p ) q —, wherein r is 0 to 10, p is 0 to 12, q is 1 to 20, and V is a single bond or —O—,
the binding unit is
wherein L 1 is a single bond or C 2-8 alkenyl, R 11 is H or C 1-6 alkyl, and L 2 is C 2-8 alkenyl; and
the connection unit is —(CH 2 ) r (V(CH 2 ) p ) q —, wherein
r is 0 to 8, p is 1 to 12, q is 1 to 10, and V is a single bond or —O—.
8. The conjugate of claim 7 , wherein the connection unit is —(CH 2 ) r (V(CH 2 ) p ) q —; r is 0, 1, or 2; p is 2, q is 2, 3, or 6; and V is O.
9. The conjugate of claim 1 , wherein Xa and Xa′ each independently a bond or C 1-3 alkyl.
10. The conjugate of claim 1 , wherein Z and Z′ are each independently selected from H,
and —(CH 2 ) m —OCH 3 .
11. The conjugate of claim 1 , wherein the ligand is a protein.
12. The conjugate of claim 11 , wherein the protein is an antibody.
13. The conjugate of claim 1 , wherein the protein has an amino acid motif represented by CYYX, XXCC, XCXC or CXX, wherein C is cysteine, Y is an aliphatic amino acid, and X is an amino acid that determines substrate specificity of an isoprenoid transferase.
14. The conjugate of claim 1 , wherein D has a structure selected from:
and the bond overlaid with a dashed line represents a connection point to L.
15. The conjugate of claim 1 , wherein:
D has a structure selected from:
the bond overlaid with a dashed line represents a connection point to L;
L is one or more units selected from a branching unit, a connection unit, and a binding unit or a combination of these units, wherein the connection unit connects W with a binding unit, W with a branching unit, a branching unit with another branching unit, or a branching unit with a binding unit, and the branching unit connects a connection unit with W or the connection unit with another connection unit;
the branching unit is a C 2-8 alkenyl, wherein a carbon atom of the alkenyl may be replaced with one or more heteroatoms selected from N, O, and S and the alkenyl may be substituted with one or more C 1-6 alkyls, a hydrophilic amino acid, —C(O)—, —C(O)NR″″—, —C(O)O—, —(CH 2 ) s —NHC(O)—(CH 2 ) t —, —(CH 2 ) u —C(O)NH—(CH 2 ) v —, —(CH 2 ) s —NHC(O)—(CH 2 ) t —C(O)—, or —(CH 2 ) u —C(O)NH—(CH 2 ) v —C(O)—, wherein R″″ is H, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl, or C 5-20 aryl and s, t, u, and v are each independently 0 to 5;
the connection unit is —(CH 2 ) r (V(CH 2 ) p ) q —, wherein r is 0 to 10, p is 0 to 12, q is 1 to 20, and V is a single bond or —O—,
the binding unit is
wherein L 1 is a single bond or C 2-8 alkenyl, R 11 is H or C 1-6 alkyl, and L 2 is C 2-8 alkenyl;
the connection unit is —(CH 2 ) r (V(CH 2 ) p ) q —, wherein
r is 0 to 8, p is 1 to 12, q is 1 to 10, and V is a single bond or —O—; and
the ligand is an antibody.
16. The conjugate of claim 15 , wherein the protein has one or more amino acid motifs that can be recognized by an isoprenoid transferase represented by CYYX, XXCC, XCXC or CXX, wherein C is cysteine, Y is an aliphatic amino acid, and X is an amino acid that determines substrate specificity of isoprenoid transferase.
17. A pharmaceutical composition comprising the conjugate of claim 1 and a pharmaceutically acceptable carrier.
18. A method of treating a proliferative disease in a subject, comprising administering the conjugate of claim 1 to the subject.