Compounds containing a vascular disrupting agent
The present invention relates to compounds, and pharmaceutically acceptable salts thereof, comprising a vascular disrupting agent (VDA) associated and a MMP proteolytic cleavage site. The compounds are useful in the treatment of cancer.
1. A peptide comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4).
2. A peptide according to claim 1 further comprising a capping group c at the N- or C-terminus of the peptide.
3. A peptide according to claim 2 , wherein c is selected from fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.
4. A prodrug comprising
a biologically active compound associated with
a peptide comprising a MMP proteolytic cleavage site comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4).
5. A prodrug according to claim 4 , wherein the biologically active compound is an anti-tumour agent or a vascular disrupting agent (VDA).
6. A prodrug according to claim 4 , wherein the peptide has a capping group c to prevent non-specific degradation of the peptide.
7. A prodrug according to claim 6 , wherein c is selected from fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.
8. A compound of
X-Y-c, or formula (II):
X-a-Y-c, or formula (IV):
X-Y-b-c, or formula (V):
X-a-Y-b-c, formula (VI):
wherein
Y is a peptide comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4),
c is a capping group,
a is a linker,
b is a spacer, and
X is an anticancer agent.
9. A compound according to claim 8 , wherein c is selected from fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.
10. A compound of claim 8 , wherein the anti-cancer agent is a vascular disrupting agent (VDA).
11. A compound of claim 8 , wherein the linker is a single amino acid or an amino acid sequence.
12. A method of producing a systemically deactivated and MMP overexpression site activatable medicament, the method comprising attaching a peptide comprising an MMP proteolytic cleavage site comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4) to the medicament.
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 -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4) and having 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 fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.
15. A method of increasing the therapeutic index of a drug, the method comprising associating the drug with a peptide comprising -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4) and having a capping group c on the N- or C-terminus, thereby reducing systemic levels of active drug and increasing the therapeutic index.
16. A method according to claim 15 , wherein c is selected from fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.
17. A method of modifying a drug, the method comprising associating the drug with a peptide comprising a MMP proteolytic cleavage site -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4) and having a capping group c on the N- or C-terminus to prevent non-specific degradation of the peptide.
18. A method according to claim 17 , wherein c is selected from fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.