Cytotoxic and anti-mitotic compounds, and methods of using the same

A compound having the following structure (Ia):

• wherein:
• R14 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —COR24, —CSR24, —OR24, and —NHR24, wherein each R24 is, independently, alkyl optionally substituted with halogen, —OH or —SH;
• R15 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
• R16 is selected from the group consisting of H and C1-6 alkyl;
• R17 is selected from the group consisting of H and C1-6 alkyl;
• R18 and R30 are independently selected from the group consisting of H, C1-6 alkyl and —SH, with the proviso that R18 and R30 cannot both be H;
• R19, R20, R21 and R22 are independently H and C1-6 alkyl, at least one of R19 and R20 is H;
• or R20 and R21 form a double bond, R19 is H, and R22 is H or C1-6 alkyl;
• and
• R23 is selected from the group consisting of H and C1-6 alkyl;
• or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof.

A compound having the following structure (Ib):

• wherein:
• R26 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
• R27 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
• R16 is selected from the group consisting of H and C1-6 alkyl;
• R17 is selected from the group consisting of H and C1-6 alkyl;
• and
• R18 is selected from the group consisting of C1-6 alkyl and —SH,
• or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof.

The composition according to claim 23, having the following structure:

• wherein,
• R1 and R2 are independently selected from the group consisting of:
• H and a saturated or unsaturated moiety having a linear, branched, or non-aromatic cyclic skeleton containing one to ten carbon atoms, and the carbon atoms are optionally substituted with:
• —OH, —I, —Br, —Cl, —F, —CN, —CO2H, —CHO, —COSH, or —NO2;
• R, and R4 are independently selected from the group consisting of:
• H, R, ArR—, or R3 and R4 are joined to form a ring;
• R31 is selected from the group consisting of:
• H, R′, ArR—, Ar—R—Ar, R—Ar—Ar, Ar—Ar—R—, and Ar, wherein each R and each Ar may be substituted, and zero to ten heteroatoms may replace carbon atoms in the chain, for example O or S or N may be incorporated into the carbon chain;
• in one embodiment, wherein R′ is
• wherein m is an integer from one to fifteen;
• R6 is selected from the group consisting of:
• H, R, and ArR—;
• R7 and R5 are independently selected from the group consisting of:
• H, R, and ArR—;
• and
• R32 is selected from:
• wherein,
• Z is defined as a moiety selected from the group consisting of:
• —OH, —OR;
• —SH;
• —SR;
• —NH2;
• —NRCH(R11)COOH;
• and —NHCH(R11)COOH, wherein R11 is a moiety having the formula:
• R, or —(CH2)nNR12R13, wherein n=1-4 and R12 and R13 are independently selected from the group consisting of:
• H;
• R;
• and —C(NH)(NH2),
• Y is defined as a moiety selected from the group consisting of:
• a linear, saturated or unsaturated, one to six carbon alkyl group, optionally substituted with R, ArR—, or X;
• and,
• X is defined as a moiety selected from the group consisting of:
• —OH, —OR, ═O, ═S, —O2CR, —SH, —SR, —SOCR, —NH2, —NHR, —N(R)2, —NHCOR, —NRCOR, —I, —Br, —Cl, —F, —CN, —CO2H, —CO2R, —CHO, —COR, —CONH2, —CONHR, —CON(R)2, —COSH, —COSR, —NO2, —SO3H, —SOR, and —SO2R;
• R14 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryls, COR24, —CSR24, —OR24, and —NHR24, wherein each R24 is, independently, alkyl optionally substituted with halogen, —OH or —SH,
• R is defined as a saturated or unsaturated moiety having a linear, branched, or non-aromatic cyclic skeleton containing one to ten carbon atoms, zero to four nitrogen atoms, zero to four oxygen atoms, and zero to four sulfur atoms, and the carbon atoms are optionally substituted with:
• ═O, ═S, OH, —OR10, —O2CR10, —SH, —SR10, —SOCR10, —NH2, —NHR10, —N(R10)2, —NHCOR10, —NR10COR10, —I, —Br, —Cl, —F, —CN, —CO2H, —CO2R10, —CHO, —COR10, —CONH2, —CONHR10, —CON(R10)2, —COSH, —COSR10, —NO2, —SO3H, —SOR10, —SO2R10, wherein R10 is a linear, branched or cyclic, one to ten carbon saturated or unsaturated alkyl group;
• the ring formed by joining R3 and R4 is a three to seven member non-aromatic cyclic skeleton within the definition of R,
• Y is defined as a moiety selected from the group consisting of:
• a linear, saturated or unsaturated, one to six carbon alkyl group, optionally substituted with R, ArR—, or X;
• and,
• X is defined as a moiety selected from the group consisting of:
• —OH, —OR, ═O, ═S, —O2CR, —SH, —SR, —SOCR, —NH2, —NHR, —N(R)2, —NHCOR, —NRCOR, —I, —Br, —Cl, —F, —CN, —CO2H, —CO2R, —CHO, —COR, —CONH2, —CONHR, —CON(R)2, —COSH, —COSR, —NO2, —SO3H, —SOR, and —SO2R;
• or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof.

A composition having the following structure:

• (T)-(L)-(PT) (VII)
• wherein (T) is a targeting moiety, (L) is an optional linker, and (PT) is a microtubule disrupting peptide toxin,
• wherein (PT) is covalently linked to (L), if (L) is present, through the side chain of the N-terminal amino acid of (PT),
• wherein (PT) is covalently linked to (T), if (L) is not present, through the side chain of the N-terminal amino acid of (PT).