Enediyne conjugates

An enediyne-glycoprotein conjugate according to general structure:

• wherein:
• Pr is an antibody;
• Z is a connecting group that is formed in a click reaction between a (hetero)cycloalkyne moiety and a 1,3-dipole;
• L6 is a linker that links Z to Pr, wherein L6 is GlcNAc(Fuc)w¬-S-(L7)w′-, wherein GlcNAc is N-acetylglucosamine, Fuc is fucose, w is 0 or 1, S is a monosaccharide, L7 is —N(H)C(O)CH2—, —N(H)C(O)CF2— or —CH2—, and w′ is 0 or 1;
• n, o, p, and q are each individually 0 or 1, provided that n+o+p+q=1, 2, 3 or 4,
• xx is an integer in the range 1-8,
• R2 is —S(C1-C10 alkyl) or —C(R6)2R7, wherein each R6 is independently selected from H or optionally substituted C1-C6 alkyl and R7 is selected from H, C1-C12 alkyl, -L5-OR8, (CH2)sO-L5-OR8 and (CH2)sC(O)NR29-L5-OR8, wherein L5 is a linker having 1-100 optionally substituted backbone atoms selected from C, N, O and S, R8 is H or methyl, s=1, 2 or 3 and R29 is selected from H and -L5-OR8;
• L1 is a linker represented by -(W)k-(A)d-(B)e-(A)f-(B)g—C(O)—, wherein:
• k=0 or 1 with the proviso that if k=1 then d=0;
• d=0 or 1;
• e=an integer in the range 1-10;
• f=0 or 1;
• g=an integer in the range 0-10;
• W is —OC(O)—, —C(O)O—, —C(O)NH—, —NHC(O)—, —OC(O)NH—, —NHC(O)O—, —C(O)(CH2)mC(O)—, —C(O)(CH2)mC(O)NH— or -(4-Ph)CH2NHC(O)(CH2)mC(O)NH—, wherein m is an integer in the range 0-10;
• A is a sulfamide group according to structure (23):
• wherein a=0 or 1, and R13 is selected from the group consisting of hydrogen, C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups, the C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR14 wherein R14 is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups, or R13 is connected to an enediyne moiety via a spacer moiety;
• B is a —CH2—CH2—O— or a —O—CH2—CH2— moiety, or (B)e is a —(CH2—CH2—O)e1—CH2—CH2— moiety, wherein e1 is defined the same way as e;
• L2 is a peptide spacer;
• L3 is a self-immolative para-aminobenzyloxycarbonyl (PABC) derivative according to structure (25):
• wherein R3 is H, R4 or C (O) R4, wherein R4 is C1-C24 (hetero)alkyl groups, C3-C10 (hetero)cycloalkyl groups, C2-C10 (hetero)aryl groups, C3-C10 alkyl(hetero)aryl groups and C3-C10 (hetero)arylalkyl groups, which are optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR5 wherein R5 is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups;
• and
• L4 is an aminoalkanoic acid spacer according to the structure —N—(Cx-alkylene)-C(O)—, wherein x is an integer in the range 1-10;
• or linker L4 is a an ethyleneglycol spacer according to the structure —N—(CH2—CH2—O)e6—(CH2)e7—C(O)—, wherein e6 is an integer in the range 1-10 and e7 is an integer in the range 1-3.