Biologically active molecules, conjugates thereof, and therapeutic uses

A method for reducing, retarding, or stopping abnormal cell growth comprising contacting one or more cells growing abnormally with a compound, in an amount sufficient to retard, reduce, or stop the abnormal cell growth, and wherein the compound has the following formula

• wherein
• L is a Ligand capable of binding to a cell or cell population;
• a is an integer from one to ten;
• Z2 is represented by the following structural formula —Z2A—Z2B—Z2C—Z2D—, wherein Z2A, Z2B, Z2C, and Z2D are each independently absent, an amino acid residue, a peptide residue having 2-20 amino acid residues, an -alkylene-, an -alkynylene-, an -alkenylene-, a -cycloalkylene-, an -arylene-, a -heteroarylene-, a -heterocyclylene-, —CR5R6—, —O—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —O—C(═O)—O—, —C(═O)—(CHx)p1—, —C(═O)—O—(CHx)p1—, —(CHx)p1—C(═O)—, —(CHx)p1—C(═O)—O—, —(O—(CH2)p2—)p3—, —((CH2)p2—O—)p3—, —C(═S)—, —C(═S)—S—, —C(═S)—NH—, —S—C(═S)—, —S—C(═S)—S—, —S—, —SO—, —SO2—, —NR4—, —N(R4)—C(═O)—N(R8)—, —N(R4)—C(═O)O—, —N(R4)—C(═O)—, —C(═O)—N(R4)—, —C(═O)—N(R4)—C(═O)—, —O—C(═O)—N(R4)—, —O—C(═S)—N(R4)—, —C(═S)—N(R4)—,
• or
• and combinations thereof or residues thereof;
• A is a natural or non-natural amino acid residue, or a peptide residue comprising 2-20 amino acid residues;
• W is —O—, —S—, —CR5R6—, or —NR4—;
• X is -arylene-, -heteroarylene-, -cycloalkylene-, or -heterocyclylene-, wherein -arylene-, -heteroarylene-, -cycloalkylene-, and -heterocyclylene- are optionally substituted;
• wherein A1 and R1 are each independently an amino acid residue, a peptide residue having 2-20 amino acid residues, an -alkylene-, an -alkynylene-, an -alkenylene-, a -cycloalkylene-, an -arylene-, a -heteroarylene-, a -heterocyclylene-, —CR5R6—, —O—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —O—C(═O)—O—, —C(═O)—(CHx)p1—, —C(═O)—O—(CHx)p1—, —(CHx)p1—C(═O)—, —(CHx)p1—C(═O)—O—, —(O—(CH2)p2—)p3—, —((CH2)p2—O—)p3—, —C(S)—, —C(═S)—S—, —S—C(S)—, —C(═S)—NH—, —S—C(═S)—S—, —S—, —SO—, —SO2—, —NR4—, —N(R4)—C(═O)—N(R8)—, —N(R4)—C(═O)O—, —N(R4)—C(═O)—, —C(═O)—N(R4)—, —C(═O)—N(R4)—C(═O)—, or —O—C(═O)—NR4—, wherein -alkylene-, -alkynylene-, -alkenylene-, -cycloalkylene-, -arylene-, -heteroarylene-, and -heterocyclylene- are optionally substituted;
• A3 is —CH2—, —CH2CH2—, or —CH2CH2CH2CH2—;
• R17 is selected from the group consisting of oxygen, sulfur, NR18, and CR5R6;
• R18 is selected from the group consisting of hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and acyl, wherein alkyl, alkynyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and acyl are optionally substituted;
• R4, R5, R6, and R8 are each independently hydrogen, or a substituted or unsubstituted:
• alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl;
• R4a is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl;
• p1, p2, and p3 are each independently zero, or an integer from one to one hundred;
• and
• x is two.

A method for killing a cell, comprising contacting the cell with a compound, in an amount sufficient to kill the cell, wherein the compound has the following formula

• wherein
• L is a Ligand capable of binding to a cell or cell population;
• a is an integer from one to ten;
• Z2 is represented by the following structural formula —Z2A—Z2B—Z2C—Z2D—, wherein Z2A, Z2B, Z2C, and Z2D are each independently absent, an amino acid residue, a peptide residue having 2-20 amino acid residues, an -alkylene-, an -alkynylene-, an -alkenylene-, a -cycloalkylene-, an -arylene-, a -heteroarylene-, a -heterocyclylene-, —CR5R6—, —O—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —O—C(═O)—O—, —C(═O)—(CHx)p1—, —C(═O)—O—(CHx)p1—, —(CHx)p1—C(═O)—, —(CHx)p1—C(═O)—O—, —(O—(CH2)p2—)p3—, —((CH2)p2—O—)p3—, —C(S)—, —C(═S)—S—, —C(═S)—NH—, —S—C(S)—, —S—C(═S)—S—, —S—, —SO—, —SO2—, —NR4—, —N(R4)—C(═O)—N(R8)—, —N(R4)—C(═O)O—, —N(R4)—C(═O)—, —C(═O)—N(R4)—, —C(═O)—N(R4)—C(═O)—, —O—C(═O)—N(R4)—, —O—C(═S)—N(R4)—, —C(═S)—N(R4)—,
• or
• and combinations thereof or residues thereof;
• A is a natural or non-natural amino acid residue, or a peptide residue comprising 2-20 amino acid residues;
• W is —O—, —S—, —CR5R6—, or —NR4—;
• X is -arylene-, -heteroarylene-, -cycloalkylene-, or -heterocyclylene-, wherein -arylene-, -heteroarylene-, -cycloalkylene-, and -heterocyclylene- are optionally substituted;
• wherein A1 and R1 are each independently an amino acid residue, a peptide residue having 2-20 amino acid residues, an -alkylene-, an -alkynylene-, an -alkenylene-, a -cycloalkylene-, an -arylene-, a -heteroarylene-, a -heterocyclylene-, —CR5R6—, —O—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —O—C(═O)—O—, —C(═O)—(CHx)p1—, —C(═O)—O—(CHx)p1—, —(CHx)p1—C(═O)—, —(CHx)p1—C(═O)—O—, —(O—(CH2)p2—)p3—, —((CH2)p2—O—)p3—, —C(S)—, —C(═S)—S—, —S—C(S)—, —C(═S)—NH—, —S—C(S)—S—, —S—, —SO—, —SO2—, —NR4—, —N(R4)—C(═O)—N(R8)—, —N(R4)—C(═O)O—, —N(R4)—C(═O)—, —C(═O)—N(R4)—, —C(═O)—N(R4)—C(═O)—, or —O—C(═O)—NR4—, wherein -alkylene-, -alkynylene-, -alkenylene-, -cycloalkylene-, -arylene-, -heteroarylene-, and -heterocyclylene- are optionally substituted;
• A3 is —CH2—, —CH2CH2—, or —CH2CH2CH2CH2—;
• R17 is selected from the group consisting of oxygen, sulfur, NR18, and CR5R6;
• R18 is selected from the group consisting of hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and acyl, wherein alkyl, alkynyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and acyl are optionally substituted;
• R4, R5, R6, and R8 are each independently hydrogen, or a substituted or unsubstituted:
• alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl;
• R4a is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl;
• p1, p2, and p3 are each independently zero, or an integer from one to one hundred;
• and
• x is two.

A method for reducing tumor size, stopping tumor size increase, reducing tumor proliferation, or preventing tumor proliferation in an individual in need thereof comprising administering to the individual an effective amount of a composition to reduce tumor size, stop tumor size increase, reduce tumor proliferation, or prevent tumor proliferation, wherein the composition comprises a compound wherein the compound has the following formula

• wherein
• L is a Ligand capable of binding to a cell or cell population;
• a is an integer from one to ten;
• Z2 is represented by the following structural formula —Z2A—Z2B—Z2C—Z2D—, wherein Z2A, Z2B, Z2C, and Z2D are each independently absent, an amino acid residue, a peptide residue having 2-20 amino acid residues, an -alkylene-, an -alkynylene-, an -alkenylene-, a -cycloalkylene-, an -arylene-, a -heteroarylene-, a -heterocyclylene-, —CR5R6—, —O—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —O—C(═O)—O—, —C(═O)—(CHx)p1—, —C(═O)—O—(CHx)p1, —(CHx)p1—C(═O)—O—, —(CHx)p1—C(═O)—O—, —(O—(CH2)p2—)p3—, —((CH2)p2—O—)p3—, —C(═S)—, —C(═S)—S—, —C(═S)—NH—, —S—C(═S)—, —S—C(═S)—S—, —S—, —SO—, —SO2—, —NR4—, —N(R4)—C(═O)—N(R8)—, —N(R4)—C(═O)O—, —N(R4)—C(═O)—, —C(═O)—N(R4)—, —C(═O)—N(R4)—C(═O)—, —O—C(═O)—N(R4)—, —O—C(═S)—N(R4)—, —C(═S)—N(R4)—,
• or
• and combinations thereof or residues thereof;
• A is a natural or non-natural amino acid residue, or a peptide residue comprising 2-20 amino acid residues;
• W is —O—, —S—, —CR5R6—, or —NR4—;
• X is -arylene-, -heteroarylene-, -cycloalkylene-, or -heterocyclylene-, wherein -arylene-, -heteroarylene-, -cycloalkylene-, and -heterocyclylene- are optionally substituted;
• wherein A1 and R1 are each independently an amino acid residue, a peptide residue having 2-20 amino acid residues, an -alkylene-, an -alkynylene-, an -alkenylene-, a -cycloalkylene-, an -arylene-, a -heteroarylene-, a -heterocyclylene-, —CR5R6—, —O—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —O—C(═O)—O—, —C(═O)—(CHx)p1—, —C(═O)—O—(CHx)p1—, —(CHx)p1—C(═O)—, —(CHx)p1—C(═O)—O—, —(O—(CH2)p2—)p3—, —((CH2)p2—O—)p3—, —C(═S)—, —C(═S)—S—, —S—C(═S)—, —C(═S)—NH—, —S—C(═S)—S—, —S—, —SO—, —SO2—, —NR4—, —N(R4)—C(═O)—N(R8)—, —N(R4)—C(═O)O—, —N(R4)—C(═O)—, —C(═O)—N(R4)—, —C(═O)—N(R4)—C(═O)—, or —O—C(═O)—NR4—, wherein -alkylene-, -alkynylene-, -alkenylene-, -cycloalkylene-, -arylene-, -heteroarylene-, and -heterocyclylene- are optionally substituted;
• A3 is —CH2—, —CH2CH2—, or —CH2CH2CH2CH2—;
• R17 is selected from the group consisting of oxygen, sulfur, NR18, and CR5R6;
• R18 is selected from the group consisting of hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and acyl, wherein alkyl, alkynyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and acyl are optionally substituted;
• R4, R5, R6, and R8 are each independently hydrogen, or a substituted or unsubstituted:
• alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl;
• R4a is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl;
• p1, p2, and p3 are each independently zero, or an integer from one to one hundred;
• and
• x is two.