Novel polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
AssigneeSLIL Biomedical Corporation
InventorsBenjamin Frydman, Laurence J. Marton
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Abstract
Peptide conjugates in which cytocidal and cytostatic agents, such as polyamine analogs or naphthoquinones, are conjugated to a polypeptide recognized and cleaved by enzymes such as prostate-specific antigen (PSA) and cathepsin B are provided, as well as compositions comprising these conjugates. Methods of using these conjugates in the treatment of prostate diseases are also provided.
Claims37
A therapeutic composition comprising a peptide substrate covalently attached to a cytostatic or cytocidal agent wherein an enzyme catalyzes cleavage of the peptide substrate from the cytostatic or cytocidal agent.
3 A composition according to claim 2, wherein the polyamine analog is linked to the peptide at the carboxy terminus of the peptide by an amide linkage to a primary or secondary amine of the polyamine.
4 A composition according to claim 2, wherein the polyamine analog contains a hydroxy group and is linked to the peptide at the carboxy terminus of the peptide by an ester linkage through said hydroxy group.
5 A composition according to claim 2, wherein the polyamine analog is of the formula:
- —N(—E)—B—A—B—NH—B—A—B—NH—B—A—B—NH—B—A—B—NH—E or —HN—B—A—B—NH—B—A—B—NH—B—A—B—NH—B—A—B—NH—E
- wherein A is independently selected from the group consisting of:
- a single bond, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl;
- B is independently selected from the group consisting of:
- a single bond, C1-C6 alkyl, and C2-C6 alkenyl;
- and E is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl;
- and any salt or stereoisomer thereof.
6 A composition according to claim 5, wherein the polyamine analog is of the formula:
- —N(—E)—B—A—B—NH—B—A—B—NH—B—A—B—NH—B—A—B—NH—E or —HN—B—A—B—NH—B—A—B—NH—B—A—B—NH—B—A—B—NH—E
- wherein A is independently selected from the group consisting of:
- a single bond, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl;
- B is independently selected from the group consisting of:
- a single bond, C1-C6 alkyl, and C2-C6 alkenyl;
- and E is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl;
- with the proviso that either at least one A moiety is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl, or at least one B moiety is selected from the group consisting of C2-C6 alkenyl;
- and any salt or stereoisomer thereof.
7 A composition according to claim 2 wherein the polyamine analog is of the formula:
- —N(—E)—B—A—B—NH—B—A—B—NH—B—A—B—NH(—B—A—B—NH)x—E or —HN—B—A—B—NH—B—A—B—NH—B—A—B—NH(—B—A—B—NH)x—E
- wherein A is independently selected from the group consisting of:
- a single bond, C6-C2 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl;
- B is independently selected from the group consisting of:
- a single bond, C1-C6 alkyl, and C2-C6 alkenyl;
- E is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl;
- and x is an integer from 2 to 16;
- and any salt or stereoisomer thereof.
A composition according to claim 7 wherein the polyamine analog is of the formula:
- —N(—E)—B—A—B—NH—B—A—B—NH—B—A—B—NH(—B—A—B—NH)x—E or —HN—B—A—B—NH—B—A—B—NH—B—A—B—NH(—B—A—B—NH)x—E
- wherein A is independently selected from the group consisting of:
- a single bond, C6-C2 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl;
- B is independently selected from the group consisting of:
- a single bond, C1-C6 alkyl, and C2-C6 alkenyl;
- E is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl;
- and x is an integer from 2 to 16;
- with the proviso that either at least one A moiety is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl, or at least one B moiety is selected from the group consisting of C2-C6 alkenyl;
- and any salt or stereoisomer thereof.
16 A composition according to claim 15 wherein the naphthoquinone contains a hydroxy group and is linked to the peptide by said hydroxy group.
17 A composition according to claim 16, where the napthoquinone is selected from the group of compounds of the formulas
- 138
- wherein A is —CH2—, —O—, —C(═O)—O—, or —O—C(═O)—, and M1 is C1-C8 alkyl, C1-C8 branched alkyl, C3-C8 cycloalkyl, or C3-C8 cycloaryl.
A composition according to claim 16, where the napthoquirrone is selected from the group of compounds of the formula
- 139
- wherein x is 1 or 2;
- and each K is independently selected from the group consisting of H, OH, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkanol, C1-C8 alkoxy, and
- 140
- with the proviso that one and only one K is selected from the group consisting of OH and C1-C8 alkanol, the peptide being conjugated to the terminal hydroxy group of the alcohol;
- and where zero or two, but no more than two, vicinal K's in the molecule represent single electrons which form a pi bond, thus forming a double bond together with the existing sigma bond between the two adjacent carbons bearing the two vicinal K's.
A composition according to claim 16, where the napthoquinone is selected from the group of compounds of the formula
- 141
- wherein Y is selected from the group consisting of —H, —F, —Br, —Cl, and —I;
- and wherein G1 is selected from the group consisting of H, C1-C8 alkyl,
- 142
- and —C(═O)—CHnX3-n, where n is an integer from 0 to 3 and X is selected from the group consisting of F, Cl, Br, and I;
- and the peptide is conjugated to the quinone via the amino group bearing G1.
A composition according to claim 16, where the napthoquinone is selected from the group of compounds of the formula
- 143
- wherein x is 1 or 2;
- and each K is independently selected from the group consisting of H, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkoxy, and
- 144
- and where zero or two, but no more than two, vicinal K's in the molecule represent single electrons which form a pi bond, thus forming a double bond together with the existing sigma bond between the two adjacent carbons bearing the two vicinal K's.
Dependencies are inferred from the claim text.