Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases

A 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, wherein the cytostatic or cytocidal agent is a conformationally restricted polyamine analog, wherein the conformational restriction is introduced by incorporation of a cyclic or unsaturated moiety between two adjacent amino groups, and 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.

A 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, wherein the cytostatic or cytocidal agent is a conformationally restricted polyamine analog, wherein the conformational restriction is introduced by incorporation of a cyclic or unsaturated moiety between two adjacent amino groups, and 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, C2-C6 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 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, wherein the cytostatic or cytocidal agent is a conformationally restricted polyamine analog, wherein the conformational restriction is introduced by incorporation of a cyclic or unsaturated moiety between two adjacent amino groups, and wherein the polyamine analog is of the formula:

• E—NH—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, 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 C1-C6 alkyl, C1-C6 alkanol, C3-C6 cycloalkanol, and C3-C6 hydroxyaryl, and the peptide is linked to the polyamine via an ester linkage at one and only one E group hydroxy;
• and x is an integer from 0 to 16;
• and any salt or stereoisomer thereof.

A 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, wherein the cytostatic or cytocidal agent is a conformationally restricted polyamine analog, wherein the conformational restriction is introduced by incorporation of a cyclic or unsaturated moiety between two adjacent amino groups, and wherein the polyamine analog is of the formula:

• —N(—E)—B—A—B—NH—F—NH—B—A—B—NH—E
• or
• —NH—B—A—B—NH—F—NH—B—A—B—NH—E
• wherein F is selected from the group consisting of C1-C6 alkyl;
• A is independently selected from the group consisting of:
• a single bond, C1-C6 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;
• 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.