Chemotherapeutic conjugates and methods of use
AssigneeRutgers, The State University of New Jersey
InventorsLongqin Hu, Xinghua Wu
Life of this patent
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Abstract
Chemotherapeutic conjugates of a peptide substrate to a phosphoramide chemotherapeutic agent in which a peptide substrate is covalently linked to the chemotherapeutic agent by a linker with an aminoarylmethyl or aminoheteroaryl moiety, wherein the linking of the peptide to the chemotherapeutic agent inhibits the cytotoxic activity of the chemotherapeutic agent, the peptide is a substrate for proteolytic cleavage by a tumor-specific enzyme; and the linker is capable of undergoing 1,6-elimination in vivo upon cleavage of the peptide substrate. Methods for synthesizing and methods of using the conjugates are also disclosed.
Claims29
A target-selective chemotherapeutic conjugate of a peptide substrate to a chemotherapeutic agent, said conjugate comprising a peptide covalently linked to the phosphoramidate group of a cytotoxic phosphoramide mustard chemotherapeutic agent by a linker comprising an aminoarylmethyl or aminoheteroaryl moiety,
- wherein the linking of said peptide substrate to said chemotherapeutic agent inhibits the cytotoxic activity of said chemotherapeutic agent;
- said peptide substrate is subject to proteolytic cleavage by a tumor-specific enzyme;
- and
- said linker is capable of undergoing 1,6-elimination in vivo upon cleavage of said peptide substrate.
A target-selective chemotherapeutic conjugate having the structure:
- wherein X is CH or N;
- R is H or an electron-withdrawing group;
- n is 0, 1, 2, 3 or 4;
- R1 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, alkoxyalkyl, carboxy-alkyl and amidoalkyl;
- at least one of R3, R4, R5 and R6 is CH2CH2Y and Y is a halogen;
- any remaining R3, R4, R5 or R6 groups may each independently be a hydrogen or a lower alkyl group;
- and said peptide substrate is subject to proteolytic cleavage by a tumor-specific enzyme.
A chemotherapeutic agent modified for peptide attachment having the structure:
- wherein X is CH or N;
- R is H or an electron-withdrawing group;
- n is 0, 1, 2, 3 or 4;
- R1 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, alkoxyalkyl, amido-alkyl and carboxylalkyl;
- and O forms a carboxylate, carbamates, phosphate, or phosphoramidate with the chemotherapeutic agent.
(canceled)
A chemotherapeutic agent modified for peptide attachment having the structure:
- wherein X is CH or N;
- R is H or an electron-withdrawing group;
- n is 0, 1, 2, 3 or 4;
- R1 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, alkoxyalkyl, amido-alkyl and carboxylalkyl;
- and O forms a carboxylate, carbamates, phosphate, or phosphoramidate bond with the chemotherapeutic agent.
(canceled)
A method for coupling a carboxylic acid and an azide comprising reacting an activated carboxylic acid with LiAlHSeH or NaHSe to form a selenocarboxylate;
- and
- reacting the selenocarboxylate with an azide to form an amide.
21-22. (canceled)
A method for synthesizing a target-selective chemotherapeutic conjugate of a peptide substrate and a chemotherapeutic agent, the method comprising:
- a) synthesizing an azide compound by a reaction that covalently bonds an azidoaryl or an azidoheteroaryl compound with a chemotherapeutic agent;
- b) reacting an N-protected amino acid selenocarboxylate and said azide compound to convert said azidoaryl or azidoheteroaryl covalently bonded to said chemotherapeutic agent to an N-protected amino acid amidoaryl or amidoheteroaryl;
- and
- c) reacting the amino acid amidoaryl or amidoheteroaryl group covalently bonded to said chemotherapeutic agent with an N-protected peptide to form a peptide substrate conjugated to said chemotherapeutic agent;
- wherein said peptide substrate is subject to proteolytic cleavage by a tumor-specific enzyme.
24-31. (canceled)
33-36. (canceled)
A target-selective chemotherapeutic conjugate of a peptide substrate to a chemotherapeutic agent, said conjugate comprising a peptide covalently linked to the cytotoxic chemotherapeutic agent by a linker of formula:
- wherein X is CH or N;
- R1 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, alkoxyalkyl, amidoalkyl and carboxylalkyl;
- O forms a carboxylate, carbamates, phosphate, or phosphoramidate with said chemotherapeutic agent;
- and Rn is selected from the group consisting of 2-F, 3-F, 2,6-di-F and 1,2,3,5-tetra-F when X is CH and 3-F, 4-F, 6-F, 3,6-di-F or 3,4,6-tri-F when X is N;
- the linking of said peptide substrate to said chemotherapeutic agent inhibits the cytotoxic activity of said chemotherapeutic agent;
- said peptide substrate is subject to proteolytic cleavage by a tumor-specific enzyme;
- and
- said linker undergoes 1,6-elimination in vivo upon cleavage of said peptide substrate.
Dependencies are inferred from the claim text.