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Peptidyl prodrugs and linkers and stabilizers useful therefor
RE41252 Peptidyl prodrugs and linkers and stabilizers useful therefor
Patent Drawings:Drawing: RE41252-10    Drawing: RE41252-11    Drawing: RE41252-12    Drawing: RE41252-13    Drawing: RE41252-14    Drawing: RE41252-15    Drawing: RE41252-16    Drawing: RE41252-17    Drawing: RE41252-18    Drawing: RE41252-19    
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(28 images)

Inventor: Ng, et al.
Date Issued: April 20, 2010
Application: 12/126,731
Filed: May 23, 2008
Inventors: Ng; Howard P. (El Sobrante, CA)
McGee; Danny P. C. (Vista, CA)
Wu; Guoxian (Foster City, CA)
Moore; Jimmie (Redwood City, CA)
Li; Zhi-Hong (Burlingame, CA)
Gangwar; Sanjeev (San Mateo, CA)
Saunder; Oliver L. (Burlingame, CA)
Astafieva; Irina (Palo Alto, CA)
Martichonok; Valeri (San Francisco, CA)
Assignee: Medarex, Inc. (Princeton, NJ)
Primary Examiner: Tsang; Cecilia
Assistant Examiner: Cordero Garcia; Marcela M
Attorney Or Agent: Darby & Darby PC
U.S. Class: 514/232.8; 514/411; 544/142; 548/429
Field Of Search:
International Class: A61K 31/535; A61K 31/407; C07D 487/02
U.S Patent Documents:
Foreign Patent Documents: 0154445; 0537575; 0689845; WO 88/04659; WO96/10405; WO97/12862; WO97/32850; WO97/45411; WO 01/16324; WO 01/49698; WO 01/74898; WO 01/83482; WO 01/85733; WO 02/083180; WO 02/088172; WO 03/022806
Other References: Colella et al., Mistmatch repair deficiency is associated with resistance to DNA minor groove alkylating agents. British Journal of Cancer.1999. vol. 80. No. 3/4. pp. 338-343.* cited by examiner.
International Search Report, issued in International Application No. PCT/US02/17210. cited by examiner.
Synthesis and Biochemical Evaluation of the CBI-PDE-I-dimer, a Benzannelated Analog of (+)-CC-1065 That Also Produces Delayed Toxicity in Mice, Paul A. Aristoff, J. Med. Chem. 1993, 36, 1956-1963. cited by examiner.
CC-1065 and the Duocarmycins: Synthetic Studies, Dale L. Boger, Chemical Review, vol. 97, No. 3, pp. 787-828. cited by examiner.
Synthesis, Chemical Properties, and Preliminary Evaluation of Substituted CBI Analogs of CC-1065 and the Duocarmycins . . . , Dale L. Boger, J. Org. Chem. 1996, 61, 4894-4912. cited by examiner.
Duocarmycin SA Shortened, Simplified, and Extended Agents: A Systematic Examination of the Role of the DNA Binding Subunit, Dale L. Boger, J. Am. Chem. Soc., vol. 119, No. 21, 1997 4979. cited by examiner.
Synthesis and Preliminary Evaluation of (+)-CC-Indole.sub.2: An Enhanced Functional Analog (+)-CC-1065, Dale L. Boger, Inorganic & Medicinal Chemistry Letters, vol. 1, No. 2, pp. 115-120, 1991. cited by examiner.
Synthesis of N-(tert-Butyloxycarbonyl)-CBI, CBI, CBI-CDPI and CBI-CDPI.sub.2: Enhanced Functional Analogues of CC-1065 Incorporating the 1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indo-4-one (CBI) Left-Hand Subunit, Dale L. Boger, Angew. J. Org. Chem,1990, 55, 5823-5832. cited by examiner.
CC-1065 and the Duocarmycins: Understanding their Biological Function through Mechanistic Studies, Dale L. Boger, Chem. Int. Ed. Engl. 1996, 35, 1438-1474. cited by examiner.
1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) Analogs of CC-1065 and the Duocarmycins: Synthesis and Evaluation, Dale L. Boger, Biorganic & Medicinal Chemistry, vol. 3, No. 11, pp. 1429 1453, 1995. cited by examiner.
Enhancement of the Selectivity and Antitumor Efficacy of a CC-1065 Analogue through Immunoconjugate Formation, Ravi V. J. Chari, Cancer Research, 55, 4079-4084, Sep. 15, 1995. cited by examiner.
Snythesis and Biological Evaluation of 2'-Carbamate--Linked and 2'-Carbonate--Linked Prodrugs of Paclitaxel: Selective Activation by the Tumor--Associated Protease Plasmin, Franciscus M.H. de Groot, J. Med. Chem. 2000, 43, 3093-3102. cited byexaminer.
Novel Synthesis of Optically Active CC-1065, U-73,975 (Adozelesin), U-80,244 (Carzelesin), U-77,779 (Bizelesin), KW-2189 and DU-86.sup.1, Yasumichi Fukuda, Heterocycles, vol. 45, No. 12, 1997. cited by examiner.
Cytotoxicity and Antitumor Activity of Carzelesin, A Prodrug Cyclopropylpyrroloindole Analogue.sup.1, L.H. Li, Cancer Research 52, 4904-4913, Sep. 15, 1992. cited by examiner.
Synthesis and Antitumor Activity of Duocarmycin Derivatives: Modification of Segment A of Duocarmycin B2, Satoru Nagamura, 1996 Pharmaceutical Society of Japan. cited by examiner.
Synthesis and Antitumor Activity of Duocarmycin Derivatives, Satoru Nagamura, Chem. Pharm. Bull, 43(9) 1530-1535 (1995). cited by examiner.
Antitumor Antibiotics: Duocarmycins, Satoru Nagamura, Chemistry of Heterocyclic Compounds, vol. 34, No. 12, 1998. cited by examiner.
Structure--Activity Relationships of (+)-CC-1065 Analogues in the Inhibition of Helicase--Catalyzed Unwinding of Duplex DNA, Daekyu Sun, Journal of Medicinal Chemistry, 1992, vol. 35, No. 10. cited by examiner.
Preparation and In Vitro Cytotoxicity of a Methotrexate-Anti-MM46 Monoclonal Antibody Conjugate Via An Oligopeptide Spacer, Naoji Umemoto, Int. J. Cancer: 43, 677-684 (1989). cited by examiner.
Dissecting the Complex Structure of CC-1065, Martha A. Warpehoski, Drugs of the Future 1991, 16(2) 131-141. cited by examiner.
Stereoelectronic Factors Influencing the Biological Activity and DNA Interaction of Synthetic Antitumor Agents Modeled on CC-1065, M.A. Warpehoski, J. Med. Chem 1988, 31, 590-603. cited by examiner.









Abstract: The present invention provides analogues of duocarmycins that are potent cytotoxins. Also provided are peptidyl and disulfide linkers that are cleaved 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.
Claim: What is claimed is:

1. A compound having the structure: ##STR00034## or a pharmaceutically acceptable salt thereof; wherein X and Z are members independently selected from O, S and NR.sup.23wherein R.sup.23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl; R.sup.1 is CO.sub.2CH.sub.3; R.sup.2 is H, or substituted or unsubstituted lower alkyl; R.sup.11 isC(O)NR.sup.12R.sup.13 in which R.sup.12, and R.sup.13 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, and at least one of R.sup.12 and R.sup.13comprises a cleaveable group; R.sup.4 and R.sup.5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl,halogen, NO.sub.2, NR.sup.15R.sup.16, NC(O)R.sup.15, OC(O)NR.sup.15R.sup.16, OC(O)OR.sup.15, C(O)R.sup.15, OR.sup.15 wherein R.sup.15 and R.sup.16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R.sup.15 and R.sup.16 together with the nitrogen atom to which theyare 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 X.sup.1 is a leaving group.

2. The compound according to claim 1, wherein said leaving group is a member selected from azide, halogen, alkylsulfonyl and arylsulfonyl groups.

3. The compound according to claim 1, wherein X.sup.1 is Cl or Br.

4. A compound having the structure: ##STR00035## or a pharmaceutically acceptable salt thereof; wherein X and Z are members independently selected from O, S and NR.sup.23 wherein R.sup.23 is a member selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl; R.sup.1 is H, substituted or unsubstituted lower alkyl, or C(O)R.sup.8, wherein R.sup.8 is a member selected from NR.sup.9R.sup.10 and OR.sup.9, in which R.sup.9 and R.sup.10 aremembers independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; R.sup.2 is CH.sub.3; R.sup.11 is C(O)NR.sup.12R.sup.13 in which R.sup.12, and R.sup.13 are members independently selected from H,substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, and at least one of R.sup.12 and R.sup.13 comprises a cleaveable group; R.sup.4 and R.sup.5 are members independently selected from H,substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO.sub.2, NR.sup.15R.sup.16, NC(O)R.sup.15, OC(O)NR.sup.15R.sup.16, OC(O)OR.sup.15,C(O)R.sup.15, OR.sup.15 wherein R.sup.15 and R.sup.16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R.sup.15 and R.sup.16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ringsystem having from 4 to 6 members, optionally containing two or more heteroatoms; and X.sup.1 is a leaving group.

5. The compound according to claim 1, wherein R.sup.1 is CO.sub.2CH.sub.3, and R.sup.2 is CH.sub.3.

6. The compound according to claim 5, wherein R.sup.4 and R.sup.5 are members independently selected from H, halogen, NH.sub.2, O(CH.sub.2).sub.2NMe.sub.2 and NO.sub.2.

7. The compound according to claim 1, wherein at least one of R.sup.4, R.sup.5, R.sup.15 and R.sup.16 comprises a cleaveable disulfide group.

8. A compound having the structure: ##STR00036## or a pharmaceutically acceptable salt thereof; wherein X and Z are members independently selected from O, S and NR.sup.23 wherein R.sup.23 is a member selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl; R.sup.1 is H, substituted or unsubstituted lower alkyl, or c(O)R.sup.8, wherein R.sup.8 is a member selected from NR.sup.9R.sup.10 and OR.sup.9, in which R.sup.9, and R.sup.10 aremembers independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; R.sup.2 is H, or substituted or unsubstituted lower alkyl; R.sup.11 is C(O)NR.sup.12R.sup.13 in which R.sup.12, and R.sup.13 aremembers independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, and at least one of R.sup.12 and R.sup.13 comprises a cleaveable group; R.sup.4 and R.sup.5 aremembers independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO.sub.2, NR.sup.15R.sup.16, NC(O)R.sup.15,OC(O)NR.sup.15R.sup.16, OC(O)OR.sup.15, C(O)R.sup.15, OR.sup.15 wherein R.sup.15 and R.sup.16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R.sup.15 and R.sup.16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted orunsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, wherein at least one of R.sup.4, R.sup.5, R.sup.15 and R.sup.16 comprises: ##STR00037## wherein R.sup.30 is a member selected from H,substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; R.sup.31 and R.sup.32 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl and substituted or unsubstituted heteroaryl, or R.sup.31 and R.sup.32 together are: ##STR00038## wherein R.sup.33 and R.sup.34 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; R.sup.35 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and NR.sup.36 wherein R.sup.36 is a member selected from H,substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and X.sup.5 is a single bond, O or NR.sup.37 wherein R.sup.37 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and X.sup.1 is a leaving group.

9. The compound according to claim 8, wherein at least one of R.sup.31, R.sup.32, R.sup.33 and R.sup.34 is substituted with a member selected from protected or unprotected reactive functional groups targeting agents and detectable labels.

10. The compound according to claim 9, wherein said targeting agent is an antibody.

11. A compound having the structure: ##STR00039## or a pharmaceutically acceptable salt thereof; wherein X and Z are members independently selected from O, S and NR.sup.23 wherein R.sup.23 is a member selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl; R.sup.1 is H, substituted or unsubstituted lower alkyl, or C(O)R.sup.8, wherein R.sup.8 is a member selected from NR.sup.9R.sup.10 and OR.sup.9, in which R.sup.9, and R.sup.10 aremembers independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; R.sup.2 is H, or substituted or unsubstituted lower alkyl; R.sup.11 is a peptidyl moiety having the structure:(L.sup.1).sub.qAA.sup.1--AA.sup.bAA.sup.b+1--(L.sup.2).sub.v--X.sup.3 wherein X.sup.3 is a member selected from protected or unprotected reactive functional groups, detectable labels and targeting agents; L.sup.1 is a linker selected from substituted orunsubstituted alkyl and substituted or unsubstituted heteroalkyl groups; AA.sup.1, AA.sup.b and AA.sup.b+1 are members independently selected from natural and unnatural .alpha.-amino acids; L.sup.2 is a linker selected from substituted or unsubstitutedalkyl 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; R.sup.4 and R.sup.5 are members independently selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO.sub.2, NR.sup.15R.sup.16, NC(O)R.sup.15, OC(O)NR.sup.15R.sup.16, OC(O)OR.sup.15, C(O)R.sup.15, OR.sup.15 whereinR.sup.15 and R.sup.16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocycloalkyl and substituted or unsubstituted peptidyl, wherein R.sup.15 and R.sup.16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4to 6 members, optionally containing two or more heteroatoms; and X.sup.1 is a leaving group.

12. The compound according to claim 11, wherein at least one of R.sup.4 and R.sup.5 is other than a member selected from H and OCH.sub.3.

13. The compound according to claim 11, wherein at least one member selected from R.sup.4, R.sup.5, R.sup.15 and R.sup.16 comprises a targeting agent or a detectable label.

14. The compound according to claim 13, wherein said targeting agent is an antibody.

15. The compound according to claim 5, wherein X is O; and Z is O.

16. A compound having the structure: ##STR00040## or a pharmaceutically acceptable salt thereof; wherein X and Z are members independently selected from O, S and NR.sup.23 wherein R.sup.23 is a member selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl; R.sup.1 is H, substituted or unsubstituted lower alkyl, or C(O)R.sup.8, wherein R.sup.8 is a member selected from NR.sup.9R.sup.10 and OR.sup.9, in which R.sup.9, and R.sup.10 aremembers independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; R.sup.2 is H, or substituted or unsubstituted lower alkyl; R.sup.11 is C(O)NR.sup.12R.sup.13 in which R.sup.12, and R.sup.13 aremembers independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, and at least one of R.sup.12 and R.sup.13 comprises a cleaveable group; R.sup.4 and R.sup.5 aremembers independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO.sub.2, NR.sup.15R.sup.16, NC(O)R.sup.15,OC(O)NR.sup.15R.sup.16, OC(O)OR.sup.15, C(O)R.sup.15, OR.sup.15 wherein R.sup.15 and R.sup.16 are independently from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R.sup.15 and R.sup.16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted orunsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, wherein a member selected from R.sup.4 and R.sup.5 is: ##STR00041## wherein X.sup.2 and Z.sup.1 are members independently selected fromO, S and NR.sup.23; R.sup.17 and R.sup.18 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocycloalkyl, halogen, NO.sub.2, NR.sup.19R.sup.20, NC(O)R.sup.19, OC(O)NR.sup.19, OC(O)OR.sup.19, C(O)R.sup.19, OR.sup.19, wherein R.sup.19 and R.sup.20 are independently selected from substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted peptidyl, wherein R.sup.19 and R.sup.20 together with the nitrogen atom towhich 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 X.sup.1 is a leaving group.

17. The compound according to claim 16, wherein X.sup.2 is O; and Z.sup.1 is a member selected from O and NR.sup.23.

18. The compound according to claim 11, wherein said peptidyl moiety has the structure: ##STR00042## wherein R.sup.21 and R.sup.22 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, detectable labels and targeting agents; R.sup.25 is a members selected from H, substituted or unsubstituted loweralkyl, an amino acid side chain, detectable labels, and targeting agents; and s is an integer from 0 to 20.

19. The compound according to claim 18, wherein b is an integer from 1 to 5.

20. A compound having the structure: ##STR00043## or a pharmaceutically acceptable salt thereof; wherein X and Z are members independently selected from O, S and NR.sup.23 wherein R.sup.23 is a member selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl; R.sup.1 is H, substituted or unsubstituted lower alkyl, or C(O)R.sup.8, wherein R.sup.8 is a member selected from NR.sup.9R.sup.10 and OR.sup.9, in which R.sup.9, and R.sup.10 aremembers independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; R.sup.2 is H, or substituted or unsubstituted lower alkyl; R.sup.11 is C(O)NR.sup.12R.sup.13 in which R.sup.12, and R.sup.13 aremembers independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, and at least one of R.sup.12 and R.sup.13 comprises a cleaveable group; R.sup.4 and R.sup.5 aremembers independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO.sub.2, NR.sup.15R.sup.16, NC(O)R.sup.15,OC(O)NR.sup.15R.sup.16, OC(O)OR.sup.15, C(O)R.sup.15, OR.sup.15 wherein R.sup.15 and R.sup.16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl, wherein R.sup.15 and R.sup.16 together with the nitrogen atom to which they are attached are optionally joined to form a substituted orunsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms, wherein at least one member selected from R.sup.15 and R.sup.16 has the structure: ##STR00044## wherein X.sup.4 is member selected fromprotected or unprotected reactive functional groups, detectable labels and targeting agents; L.sup.3 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups; AA.sup.1, AA.sup.c and AA.sup.c+1 aremembers independently selected from natural and unnatural .alpha.-amino acids; L.sup.4 is a linker selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl; R.sup.24 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 and1; and c is an integer from 0 to 20; X.sup.1 is a leaving group; and wherein represents a point at which R.sup.15 or R.sup.16 is attached to a remainder of the compound.

21. The compound according to claim 20, wherein said member has the structure: ##STR00045## wherein R.sup.27 and R.sup.28 are members independently selected from H, substituted or unsubstituted lower alkyl, amino acid side chains, detectablelabels and targeting agents; and s is an integer in the range of 0 to 6.

22. The compound according to claim 20, wherein c is an integer from 1 to 5.

23. The compound according to claim 11 or 20, wherein said detectable label is a fluorophore.

24. The compound according to claim 11 or 20, wherein said targeting agent is a biomolecule.

25. The compound according to claim 24, wherein said biomolecule is a member selected from antibodies, receptors, peptides, lectins, saccharides, nucleic acids and combinations thereof.

26. The compound according to claim 18, wherein at least one of R.sup.21 and R.sup.22 bears a reactive functional group appropriate for conjugating said compound to another molecule.

27. The compound according to claim 26 wherein at least one of R.sup.21 and R.sup.22 is a member selected from substituted alkyl and substituted heteroalkyl, said member having said reactive functional group at its free terminus.

28. The compound according to claim 26, wherein said compound is conjugated to said another molecule via said reactive functional group.

29. A pharmaceutical formulation comprising a compound according to claim 15 and a pharmaceutically acceptable carrier.

30. A method of killing a cell, said method comprising administering to said cell an amount of a compound according to claim 11 sufficient to kill said cell.

31. 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 11, sufficient to kill said cell.

32. 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 11, sufficient to retard or stop said growth.
Description:
 
 
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