Compounds

Abstract

The present invention relates to prodrugs of vascular disrupting agents comprising a vascular disrupting agent (VDA) associated with a MMP proteolytic cleavage site and to the use of such prodrugs in the targeted treatment of cancer.

What is claimed: 
     
         1 . A method to treat a disease or condition associated with tissue over-expressing an MT-MMP in a subject comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, comprising a vascular disrupting agent (VDA) associated with a matrix metalloproteinase (MMP) proteolytic cleavage site, wherein the VDA is selected from the group consisting of azademethylcolchicine, colchicine, azacolchicine, N-methyl desacetylcolchicine, desacetylcolchicine, N-acetylcolchinol-O-phosphate, colchicinoids, combrestatins, phenstatin, podophyllotoxins, steganacins, amphethinile, stilbenes, flavonoids, vincristine, vinblastine, vinflunine, maytansinoids, phomopson A, rhizoxin, auristatin, and dolstatin and the MMP proteolytic cleavage site comprises the amino acid sequence -Leu-P2′-Hof-Gly-Cit-Ser-Arg-, wherein P2′ is an amino acid selected from Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr. 
     
     
         2 . A method according to  claim 1 , wherein the disease or condition is selected from cancer, inflammatory disorders, heart failure and wounds. 
     
     
         3 . A method according to  claim 2 , wherein the disease or condition is cancer. 
     
     
         4 . A method according to  claim 1 , wherein the VDA is selected from azademethylcolchicine, colchicine, azacolchicine, N-methyl desacetylcolchicine, or desacetylcolchicine. 
     
     
         5 . A method according to  claim 1 , wherein the compound further comprises a capping group c on the N- or C-terminus of the peptide which prevents non-specific degradation of the peptide by enzymes other than MMPs. 
     
     
         6 . A peptide comprising an MMP proteolytic cleavage site comprising the amino acid sequence -Leu-P2′-Hof-Gly-Cit-Ser-Arg-, wherein P2′ wherein P2′ is an amino acid selected from Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr. 
     
     
         7 . A peptide according to  claim 6  further comprising a capping group c at the N- or C-terminus of the peptide. 
     
     
         8 . A peptide according to  claim 7 , wherein c is selected from aliphatics, aromatics, polycyclics, carbohydrates, amino acids and fluorescein. 
     
     
         9 . A prodrug comprising:
 a biologically active compound associated with a peptide comprising the amino acid sequence -Leu-P 2′-Hof-Gly-Cit-Ser-Arg-, wherein P 2′ is an amino acid selected from Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr.   
     
     
         10 . A prodrug according to  claim 9  further comprising a capping group c at the N- or C-terminus of the peptide. 
     
     
         11 . A prodrug according to  claim 10 , wherein c is selected from aliphatics, aromatics, polycyclics, carbohydrates, amino acids and fluorescein. 
     
     
         12 . A prodrug according to any one of  claims 9  to  11 , wherein the biologically active compound is an anti-cancer agent or a vascular disrupting agent (VDA). 
     
     
         13 . A method of modifying a drug to overcome a toxic effect of systemic administration of the drug, comprising associating the drug with a peptide comprising a MMP proteolytic cleavage site -Leu-P 2′-Hof-Gly-Cit-Ser-Arg- wherein P 2′ is an amino acid selected from Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr and wherein the peptide has a capping group c on the N- or C-terminus to prevent non-specific degradation of the peptide. 
     
     
         14 . A method according to  claim 13 , wherein c is selected from the group consisting of aliphatics, aromatics, polycyclics, carbohydrates, amino acids and fluorescein.