CA2448319A1 - Cytotoxins, prodrugs, linkers and stabilizers useful therefor - Google Patents
Cytotoxins, prodrugs, linkers and stabilizers useful therefor Download PDFInfo
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- CA2448319A1 CA2448319A1 CA002448319A CA2448319A CA2448319A1 CA 2448319 A1 CA2448319 A1 CA 2448319A1 CA 002448319 A CA002448319 A CA 002448319A CA 2448319 A CA2448319 A CA 2448319A CA 2448319 A1 CA2448319 A1 CA 2448319A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Abstract
The present invention provides analogues of duocarmycins that are potent cytotoxins. Also provided are peptidyl and disulfide linkers that are cleave d in vivo. The linkers are of use in forming prodrugs and conjugates of the cytotoxins of the invention as well as other diagnostic and therapeutic moieties. The invention provides prodrugs and conjugates of the duocarmycin analogues with the linker arms of the invention.
Claims (47)
1. A compound having the structure:
wherein X and Z are members independently selected from O, S and NR23 wherein R23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
R1 is H, substituted or unsubstituted lower alkyl, or C(O)R8, wherein R8 is a member selected from NR9R10 and OR9, in which R9, and R10 are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
R2 is H, or substituted or unsubstituted lower alkyl;
R3 is a member selected from (=O), and OR11, wherein R11 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, acyl, C(O)R12R13, C(O)OR12, C(O)NR12R13, C(O)OR12, P(O)(OR12)2, C(O)CHR12R13, C(O)OR12 and SiR12R13R14, in which R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, wherein R12 and R13 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, and one or more of R12, R13, and R14 optionally comprises an enzymatically cleaveable group;
R4 and R5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, OR15 wherein R15 and R16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R15 and R16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms;
R6 is a single bond which is either present or absent and when present R6 and R7 are joined to form a cyclopropyl ring; and R7 is CH2-X1 or -CH2- joined in said cyclopropyl ring with R7, wherein X1 is a leaving group.
wherein X and Z are members independently selected from O, S and NR23 wherein R23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
R1 is H, substituted or unsubstituted lower alkyl, or C(O)R8, wherein R8 is a member selected from NR9R10 and OR9, in which R9, and R10 are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
R2 is H, or substituted or unsubstituted lower alkyl;
R3 is a member selected from (=O), and OR11, wherein R11 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, acyl, C(O)R12R13, C(O)OR12, C(O)NR12R13, C(O)OR12, P(O)(OR12)2, C(O)CHR12R13, C(O)OR12 and SiR12R13R14, in which R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, wherein R12 and R13 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, and one or more of R12, R13, and R14 optionally comprises an enzymatically cleaveable group;
R4 and R5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, OR15 wherein R15 and R16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R15 and R16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms;
R6 is a single bond which is either present or absent and when present R6 and R7 are joined to form a cyclopropyl ring; and R7 is CH2-X1 or -CH2- joined in said cyclopropyl ring with R7, wherein X1 is a leaving group.
2. The compound according to claim 1, wherein R2 is other than CF3.
3. The compound according to claim 1, wherein said leaving group is a member selected from azide, halogen, alkylsulfonyl and arylsulfonyl.
4. The compound according to claim 3, wherein said leaving group is Cl or Br.
5. The compound according to claim 1, wherein R1 is CO2CH3.
6. The compound according to claim 1, wherein R2 is CH3.
7. The compound according to claim 1, wherein R1 is CO2CH3, and R2 is CH3.
8. The compound according to claim 7, wherein R4 and R5 are members independently selected from H, halogen, NH2, O(CH2)2N(Me)2 and NO2.
9. The compound according to claim 1, wherein at least one of R4 and R5 is other than a member selected from H and OCH3.
10. The compound according to claim 1, wherein at least one of R4, R5, R15 and R16 comprises a cleaveable disulfide group.
11. The compound according to claim 1, wherein at least one of R4, R5, R15 and R16 comprises:
wherein R30 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
R31 and R32 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, or R31 and R32 together are:
wherein R33 and R34 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R35 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and NR36 wherein R36 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and X5 is O or NR37 wherein R37 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.
wherein R30 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
R31 and R32 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, or R31 and R32 together are:
wherein R33 and R34 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R35 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and NR36 wherein R36 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and X5 is O or NR37 wherein R37 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.
12. The compound according to claim 11, wherein at least one of R31, R32 R33 and R34 is substituted with a member selected from targeting agents and detectable labels.
13. The compound according to claim 12, wherein said targeting agent is an antibody.
14. The compound according to claim 1, wherein at least one member selected from R4, R5, R15 and R16 comprises a targeting agent or a detectable label.
15. The compound according to claim 14, wherein said targeting agent is an antibody.
16. The compound according to claim 7, having the structure:
17. The compound according to claim 7, wherein X is O; and Z is O.
18. The compound according to claim 1, wherein a member selected from R4 and R5 is:
wherein X2 and Zl are members independently selected from O, S and NR23.
R17 and Rl8 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2,NR19R20, NC(O)R19, OC(O)NRl9, OC(O)OR19, C(O)R19, OR19 wherein R19 and R20 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted peptidyl, wherein R19 and R20 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, and one or more members selected from R19 and R20 comprise a cleaveable group.
wherein X2 and Zl are members independently selected from O, S and NR23.
R17 and Rl8 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2,NR19R20, NC(O)R19, OC(O)NRl9, OC(O)OR19, C(O)R19, OR19 wherein R19 and R20 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted peptidyl, wherein R19 and R20 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, and one or more members selected from R19 and R20 comprise a cleaveable group.
19. The compound according to claim 18, wherein when Zl is NH, both Rl7 and Rl8 are not H; and Rl7 is not NH2.
20. The compound according to claim 18, wherein X2 is O; and Zl is a member selected from O and NR23.
21. The compound according to claim 1, wherein R11 is a peptidyl moiety having the structure:
wherein X3 is a member selected from protected or unprotected reactive functional groups, detectable labels and targeting agents;
L1 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
AA1, AAb and AAb+1 are members independently selected from natural and unnatural a-amino acids;
L2 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
q and v are integers independently selected from 0 and 1; and b is an integer from 0 to 20.
wherein X3 is a member selected from protected or unprotected reactive functional groups, detectable labels and targeting agents;
L1 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
AA1, AAb and AAb+1 are members independently selected from natural and unnatural a-amino acids;
L2 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
q and v are integers independently selected from 0 and 1; and b is an integer from 0 to 20.
22. The compound according to claim 21, wherein at least one member selected from L3 and L4 comprises a poly(ethylene glycol) moiety.
23. The compound according to claim 21, wherein said peptidyl moiety has the structure:
wherein R21 and R22 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, detectable labels and targeting agents;
R25 is a members selected from H, substituted or unsubstituted lower alkyl, an amino acid side chain, detectable labels, and targeting agents; and s is an integer from 0 to 20.
wherein R21 and R22 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, detectable labels and targeting agents;
R25 is a members selected from H, substituted or unsubstituted lower alkyl, an amino acid side chain, detectable labels, and targeting agents; and s is an integer from 0 to 20.
24. The compound according to claim 21, wherein c is an integer between 1 and 5.
25. The compound according to claim 21, wherein at least one member selected from R15 and R16 has the structure:
wherein X4 is member selected from protected or unprotected reactive functional groups, detectable labels and targeting agents;
L3 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
AA1, AA c and AA c+1 are members independently selected from natural and unnatural .alpha.-amino acids;
L4 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
R24 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
p and t are integers independently selected from 0 and 1; and c is an integer from 0 to 20.
wherein X4 is member selected from protected or unprotected reactive functional groups, detectable labels and targeting agents;
L3 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
AA1, AA c and AA c+1 are members independently selected from natural and unnatural .alpha.-amino acids;
L4 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
R24 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
p and t are integers independently selected from 0 and 1; and c is an integer from 0 to 20.
26. The compound according to claim 25, wherein at least one member selected from L1 an L2 comprises a poly(ethylene glycol) moiety.
27. The compound according to claim 25, wherein said member has the structure:
wherein R27 and R28 are members independently selected from H, substituted or unsubstituted lower alkyl, amino acid side chains, detectable labels and targeting agents.
wherein R27 and R28 are members independently selected from H, substituted or unsubstituted lower alkyl, amino acid side chains, detectable labels and targeting agents.
28. The compound according to claim 25, wherein c is an integer from 1 to 5.
29. The compound according to claim 1 or 25, wherein R11 has the structure:
wherein X4 is a member selected from protected reactive functional groups, unprotected reactive functional groups, detectable labels and targeting agents;
L3 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
L4 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups; and p and t are integers independently selected from 0 and 1.
wherein X4 is a member selected from protected reactive functional groups, unprotected reactive functional groups, detectable labels and targeting agents;
L3 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
L4 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups; and p and t are integers independently selected from 0 and 1.
30. The compound according to claim 29, wherein L4 is a substituted or unsubstituted ethylene moiety.
31. The compound according to claim 29, wherein X4 is a member selected from R29, COOR29, C(O)NR29, and C(O)NNR29 wherein R29 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted heteroaryl.
32. The compound according to claim 31, wherein R29 is a member selected from: H; OH; NHNH2;
wherein R30 is a member selected from substituted or unsubstituted alkyl terminated with a reactive functional group, substituted or unsubstituted heteroaryl terminated with a functional group and -(L3)p X4, wherein each L3, X4 and p are independently selected.
wherein R30 is a member selected from substituted or unsubstituted alkyl terminated with a reactive functional group, substituted or unsubstituted heteroaryl terminated with a functional group and -(L3)p X4, wherein each L3, X4 and p are independently selected.
33. The compound according to claim 21, 25, or 29, wherein said detectable label is a fluorophore.
34. The compound according to claim 21, 25, or 29, wherein said targeting agent is a biomolecule.
35. The compound according to claim 34, wherein said biomolecule is a member selected from antibodies, receptors, peptides, lectins, saccharides, nucleic acids and combinations thereof.
36. The compound according to claim 1, wherein at least one of R15 and R16 bears a reactive group appropriate for conjugating said compound to another molecule.
37. The compound according to claim 36 wherein at least one of R15 and R16 is a member selected from substituted alkyl and substituted heteroalkyl, said member having said reactive functional group at its free terminus.
38. The compound according to claim 36, wherein said compound is conjugated to said another molecule via said reactive functional group.
39. The compound according to claim 1, wherein one of R15 and R16 comprises a cleaveable moiety.
40. The compound according to claim 27, wherein at least one of R21 and R22 bears a reactive functional group appropriate for conjugating said compound to another molecule.
41. The compound according to claim 36 wherein at least one of R21 and R22 is a member selected from substituted alkyl and substituted heteroalkyl, said member having said reactive functional group at its free terminus.
42. The compound according to claim 36, wherein said compound is conjugated to said another molecule via said reactive functional group.
43. A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
44. A method of killing a cell, said method comprising administering to said cell an amount of a compound according to claim 1 sufficient to kill said cell.
45. A method of killing a carcinoma cell in a subject bearing said cell, said method comprising administering to said subject an amount of a compound according to claim 1, sufficient to kill said cell.
46. A method of retarding or stopping the growth a tumor in a mammalian subject, said method comprising administering to said subject an amount of a compound according to claim 1, sufficient to retard or stop said growth.
47. A compound having the structure:
in which ring system A is a member selected from substituted or unsubstituted aryl substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl groups;
E and G are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, a heteroatom, or a single bond, and E and G are optionally joined to form a ring system selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;
X is a member selected from O, S and NR23, R23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
R3 is a member selected from (=O), SR11 and OR11 in which R11 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, acyl, C(O)R12, C(O)OR12, C(O)NR12R13, C(O)OR12, P(O)(OR12)2, C(O)CHR12R13, C(O)OR12 or SiR12R13R14, and R11 optionally comprises an enzymatically cleaveable group wherein R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, wherein R12 and R13 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, and one or more of R12, R13, or R14 optionally comprises an enzymatically cleaveable group; and R4 and R5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, SR15 and OR15. R15 and R16 independently represent H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R15 and R16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, and one or more of R4, R5, R15 and R16 optionally comprise an enzymatically cleaveable group.
in which ring system A is a member selected from substituted or unsubstituted aryl substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl groups;
E and G are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, a heteroatom, or a single bond, and E and G are optionally joined to form a ring system selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;
X is a member selected from O, S and NR23, R23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
R3 is a member selected from (=O), SR11 and OR11 in which R11 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, acyl, C(O)R12, C(O)OR12, C(O)NR12R13, C(O)OR12, P(O)(OR12)2, C(O)CHR12R13, C(O)OR12 or SiR12R13R14, and R11 optionally comprises an enzymatically cleaveable group wherein R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, wherein R12 and R13 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, and one or more of R12, R13, or R14 optionally comprises an enzymatically cleaveable group; and R4 and R5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, SR15 and OR15. R15 and R16 independently represent H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R15 and R16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, and one or more of R4, R5, R15 and R16 optionally comprise an enzymatically cleaveable group.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US29534201P | 2001-05-31 | 2001-05-31 | |
| US29525901P | 2001-05-31 | 2001-05-31 | |
| US29519601P | 2001-05-31 | 2001-05-31 | |
| US60/295,259 | 2001-05-31 | ||
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