Prodrugs of CC-1065 analogs
Prodrugs of analogs of the anti-tumor antibiotic CC-1065 having a cleavable protective group such as a piperazino carbamate, a 4-piperidino-piperidino carbamate or a phosphate, in which the protecting group confers enhanced water solubility and stability upon the prodrug, and in which the prodrug also has a moiety, such as a disulfide, that can conjugate to a cell binding reagent such as an antibody. The therapeutic use of such prodrug conjugates is also described; such prodrugs of cytotoxic agents have therapeutic use because they can deliver cytotoxic prodrugs to a specific cell population for enzymatic conversion to cytoxic drugs in a targeted fashion.
1. A prodrug of an analog of CC-1065, having three subunits linked by amide bonds, wherein the first subunit is a seco-CBI (cyclopropabenzindole) molecule represented by the following formula:
wherein X is halogen, and
wherein the second and third subunits together are represented by the formula (II):
wherein R represents a linking group that enables linkage of said prodrug to a cell binding agent; R 1 -R 6 are each independently hydrogen, C 1 -C 3 linear alkyl, methoxy, hydroxyl, primary amino, secondary amino, tertiary amino, or amido; and R 7 is piperazine carbamate, 4-piperidino-piperidino carbamate or phosphate, and
wherein the compound of formula (I) is covalently bonded the compound of formula (II) via the secondary amino group of the pyrrole moiety of the first subunit to the C-2 carboxyl of the second subunit.
2. The prodrug of claim 1 , wherein R comprises a thiol or a disulfide bond.
3. The prodrug of claim 1 , wherein the linking group is selected from the group consisting of NHCO(CH 2 ) m SZ, NHCOC 6 H 4 (CH 2 ) m SZ, NHCOC 6 H 4 O(CH 2 ) m SZ, NHCO(CH 2 ) m (OCH 2 CH 2 ) n SZ, NHCOC 6 H 4 (CH 2 ) m (OCH 2 CH 2 ) n SZ, and NHCOC 6 H 4 O(CH 2 ) m (OCH 2 CH 2 ) n SZ wherein: Z represents H or SR 8 , wherein R 8 represents methyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl or heterocyclic selected from the group consisting of furyl, pyrrollyl, pyridyl, and thiophene, m represents an integer of 1 to 10, and n represents an integer of 4 to 1000.
4. The prodrug of claim 1 , wherein the linking group is selected from the group consisting of NHCO(CH 2 ) m (OCH 2 CH 2 ) n SZ, NHCOC 6 H 4 (CH 2 ) m (OCH 2 CH 2 ) n SZ, and NHCOC 6 H 4 O(CH 2 ) m (OCH 2 CH 2 ) n SZ wherein: Z represents H or SR 8 , wherein R 8 represents methyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl or heterocyclic selected from the group consisting of furyl, pyrrollyl, pyridyl, and thiophene, m represents an integer of 1 to 10, and n represents an integer from 2 to 1000.
5. The prodrug of claim 3 , wherein the linking group is selected from the group consisting of NHCO(CH 2 ) 2 SH, NHCO(CH 2 ) 2 SSCH 3 , NHCO(CH 2 ) 2 (OCH 2 CH 2 ) n SH and NHCO(CH 2 ) 2 (OCH 2 CH 2 ) n SSCH 3 .
6. The prodrug of claim 1 , wherein the first subunit is represented by formula (I):