Peptides with anti-cancer activity

A peptide, or pharmaceutical salt thereof or active metabolite thereof, of formula (I):

• wherein
• one of m, n, p, and q is 1 and the others are 0,
• j is 1,
• v is an integer from 1 to 10, and
• L corresponds to a birradical of formula (II)
• —P—[(R1)a—(R2)—(R3)b]c-Q- (II)
• wherein
• “a” and “b” are the same or different and are 0 or 1;
• “c” is an integer from 1 to 10;
• R1 and R3 are dirradicals independently selected from the group consisting of:
• (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkyl-O—(C1-C10)alkyl, (C1-C10)alkyl-C(═O)—(C1-C10)alkyl, (C1-C10)alkyl-O—C(O)—(C1-C10)alkyl, (C1-C10)alkyl-C(O)—NR8—(C1-C10)alkyl, (C1-C10)alkyl-S—(C1-C10)alkyl, (C1-C10)alkyl-SR9—(C1-C10)alkyl, (C1-C10)alkyl-S(═O)2—(C1-C10)alkyl, (C1-C10)alkyl-S(═O)—(C1-C10)alkyl, (C1-C10)alkyl-O—S(═O)2—O—(C1-C10)alkyl, and (C1-C10)alkyl-NR10—(C1-C10)alkyl;
• R2 is a dirradical selected from the group consisting of:
• O, C(═O), C(═O)R4, C(═O)NR5, C(═O)O, S(═O), S(═O)2, S(R6), N(R7), (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, NR13R14, —NH—NH—, —N═N—, —S—S—, and a known ring system comprising from 3 to 14 carbon atoms, the system comprising from 1 to 3 rings, where:
• each one of the rings is saturated, partially unsaturated, or aromatic;
• the rings are isolated, partially or totally fused,
• each one of the members forming the known ring system is selected from the group consisting of:
• —CH—, —CH2—, —NH—, —N—, —SH—, —S—, and —O—;
• and
• the ring system is optionally substituted by one or more radicals independently selected from the group consisting of halogen, —OH, —NO2, (C1-C10)haloalkyl, and (C1-C10)alkyl-O—;
• R4, R5, R6, R7, R8, R9, R10, R13, and R14 are monoradicals selected from the group consisting of:
• hydrogen, (C1-C10)alkyl, (C2-C10)alkenyl, and (C2-C10)alkynyl;
• P and Q are birradicals, the same or different, provided that
• when “a” and “b” are 0, or alternatively one of “a” and “b” is 0, then P and Q have a meaning different from R2 radical, said P and Q birradicals being selected from the group consisting of:
• (C1-C10)alkyl, (C2-C10)alkenyl, and (C2-C10)alkynyl;
• or, alternatively,
• when “a” and “b” are 0, or alternatively one of “a” and “b” is 0, then P and Q are C(═O), and R2 is selected from the group consisting of:
• —O—, S(R6), N(R7), (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, —NR13R14, —NH—NH—, —N═N—, —S—S—, and a known ring system comprising from 3 to 14 carbon atoms, the system comprising from 1 to 3 rings, where:
• each one of the rings is saturated, partially unsaturated, or aromatic;
• the rings are isolated, partially or totally fused,
• each one of the members forming the known ring system is selected from the group consisting of:
• —CH—, —CH2—, —NH—, —N—, —SH—, —S—, and —O—;
• and
• the ring system is optionally substituted by one or more radicals independently selected from the group consisting of halogen, —OH, —NO2, (C1-C10)alkyl, (C1-C10)haloalkyl, and (C1-C10)alkyl-O—;
• when both “a” and “b”, are 1, then P and Q are selected from the group consisting of:
• —S—, (C1-C10)alkyl-S—, —NR′10—, (C1-C10)alkyl-NR′10′, —O—, (C1-C10)-alkyl-O—, —C(═O), (C1-C10)alkyl-C(═O)—, —C(═O)O, (C1-C10)alkylC(═O)O—, C(═O)N—, (C1-C10)alkylC(═O)—, C(═O)S— and (C1-C10)alkyl-C(═O)S— being R′10 a radical selected from the group consisting of:
• hydrogen, (C1-C10)alkyl, (C2-C10)alkenyl, and (C1-C10)alkynyl;
• the L birradical being bound to the backbone of the peptide sequence of formula (I) via X1 and X3 birradicals, or alternatively via X1 and X5 birradicals, or alternatively via X2 and X4 birradicals, or alternatively via X3 and X6 birradicals,
• the X birradicals which are bound to L birradical having the same or different meaning and being of formula (III):
• wherein
• the L birradical binds to the X birradical of formula (III) via the alpha carbon atom;
• R11 is a monoradical selected from the group consisting of:
• (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkyl-O—(C1-C10)alkyl, (C1-C10)alkyl-C(═O)—(C1-C10)alkyl, (C1-C10)alkyl-O—C(O)—(C1-C10)alkyl, (C1-C10)alkyl-C(O)—NR8—(C1-C10)alkyl, (C1-C10)alkyl-S—(C1-C10)alkyl, (C1-C10)alkyl-SR9—(C1-C10)alkyl, (C1-C10)alkyl-S(═O)2—(C1-C10)alkyl, (C1-C10)alkyl-S(═O)—(C1-C10)alkyl, (C1-C10)alkyl-O—S(═O)2—O—(C1-C10)alkyl, (C1-C10)alkyl-NR10—(C1-C10)alkyl, and a known ring system comprising from 3 to 14 carbon atoms, the system comprising from 1 to 3 rings, where:
• each one of the rings is saturated, partially unsaturated, or aromatic;
• the rings are isolated, partially or totally fused,
• each one of the members forming the known ring system is selected from the group consisting of:
• —CH—, —CH2—, —NH—, —N—, —SH—, —S—, and —O—;
• and
• the ring system is optionally substituted by one or more radicals independently selected from the group consisting of halogen, —OH, —NO2, (C1-C10)alkyl, (C1-C10)haloalkyl, and (C1-C10)alkyl-O—,
• and the other X birradicals of the backbone peptide sequence of formula (I), which are not bound to the “L” birradical, are the same or different and represent amino acids;
• provided that at least one of the X birradicals not bound to the “L” birradical is selected from the group consisting of:
• X1 represents an amino acid other than Glu,
• X2 represents an amino acid other than Lys,
• X3 represents an amino acid other than Ser,
• X4 represents an amino acid other than Phe,
• X5 represents an amino acid other than Ala, and
• X6 represents an amino acid other than Gln;
• wherein:
• the (C1-C10)alkyl, (C2-C10)alkenyl, and (C2-C10)alkynyl are non-substituted or substituted,
• “substituted (C1-C10)alkyl” means that the (C1-C10)alkyl is substituted by one or more radicals selected from the group consisting of:
• halogen, —OR′11, —NO2, —NR′11R12, —SR′11, —SO2R′11, —CO2R′11, and (C1-C10)alkyl-O—, being R′11 and R12 the same or different and selected from the group consisting of:
• —H, (C1-C10)alkyl, (C2-C10)alkenyl, and (C1-C10)alkynyl;
• “substituted (C2-C10)alkenyl” means that the (C2-C10)alkenyl is substituted by one or more radicals selected from the group consisting of:
• halogen, —OR′11, —NO2, —NR′11R12, —SR′11, —SO2R′11, —CO2R′11, and (C1-C10)alkyl-O—, being R′11 and R12 the same or different and selected from the group consisting of:
• —H, (C1-C10)alkyl, (C2-C10)alkenyl, and (C1-C10)alkynyl;
• and
• “substituted (C2-C10)alkynyl” means that the (C2-C10)alkynyl is substituted by one or more radicals selected from the group consisting of:
• halogen, —OR′11, —NO2, —NR′11R12, —SR′11, —SO2R′11, —CO2R′11, and (C1-C10)alkyl-O—, being R′11 and R12 the same or different and selected from the group consisting of:
• —H, (C1-C10)alkyl, (C2-C10)alkenyl, and (C1-C10)alkynyl;
• and
• the active metabolite lacks the first amino acid of the N-terminal region and/or from 1 to 3 amino acids of the C-terminal region.