P-selectin targeting ligand and compositions thereof

A targeting ligand molecule comprising:

• a target recognizing moiety
• a spacer, which is formed from a water soluble oligomer or polymer and
• an anchoring moiety, which is formed from an amphiphilic lipid, consisting of at least one hydrophobic apolar moiety and a hydrophilic polar head group, wherein wherein the target recognizing moiety is derived from:
• (1) a peptide, peptoid or derivative thereof having an amino acid sequence X (Ax)mA3A1A2A1Y, or a functional equivalent of said sequence, wherein:
• A1 is a D- or L-cysteine (C), D- or L-valine (V) or an analogue thereof;
• A2 is a D- or L-aspartic acid (D) or an analogue thereof;
• A3 is a D- or L-phenylalanine (F), or D- or L-tryptophan (W) or an analogue thereof;
• Ax is a D- or L-amino acid, selected from the group consisting of glutamic acid (E), aspartic acid (D), glycine (G) and cysteine (C);
• X marks the N-terminal side of said sequence and is hydrogen or a residue comprising 1 to 6 D- or L-amino acids or analogues thereof;
• Y marks the C-terminal side of said sequence and is —OH or a residue comprising 1 to 11 D- or L-amino acids or analogues thereof;
• wherein X and Y together can form a cyclic system;
• wherein wherein at least one of X and Y or X+Y is substituted with the group R1-(Z)n- wherein:
• Z is selected from —CO—, —O—, —NR2—, and —CO—NR2—;
• wherein R1 and R2 are independently selected from:
• a) H;
• b) a C1-C8 alkyl group;
• c) a C2-C8 alkyl group, wherein at least one C-atom is replaced with a nitrogen, oxygen or sulphur atom;
• d) a C6-C14 aryl group, which is optionally substituted with at least one group selected from a halogen, C1-C6-alkyl, —CF3, —OH, —O—C1-C6-alkyl, —COOH, —COO—C1-C6-alkyl, —NO2, —NH2, —NH—C1-C6-alkyl, —N—(C1-C6-alkyl)2 and —SO3H;
• e) a heteroaryl group which is selected from 5- or 6-membered ring systems and benzo- condensed ring systems, and has at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, wherein said heteroaryl group is optionally substituted with at least one group selected from the group consisting of a halogen, —C1-C6-alkyl, —CF3, —OH, —O—C1-C6-alkyl, —COOH, —COO—C1-C6-alkyl, —NO2, —NH5, —NH—C1-C6-alkyl, —N—(C1-C6-alkyl)2 and —SO3H;
• f) an aralkyl group comprising an alkyl group as defined in b) or c) and an aryl group or heteroaryl group as defined in d) or e);
• and
• m and n are integers independently selected from 0 and 1, with the proviso that n is not 0 when R1 is H.
• (2) a compound represented by the following formula Ia:
• and its stereo-isomer, represented by the following formula Ib:
• wherein:
• X is an optional group, which represents —O—, —OCH2—, —S—, —SCH2—, —NH— or —NHCH2—;
• R1 represents QR4, wherein Q represents —O—, —NH—, —NH—(C═O)—, —O—(C═O), —NH—(C═O)—O— or —NH—(C═O)—NH—;
• and wherein R4 represents H or any compound comprising at least one carbon atom;
• R2 is a moiety bearing at least one negative charge and
• R3 can be any group, provided that if Q=-O— and R4 is —H—, X is present,
• (3) gallic acid or a derivative thereof, a polyphenol or a polyhydroxy phenol of structural formula II:
• wherein:
• R1=a hydrogen;
• a straight or branched (C1-C4) aliphatic alkyl group or an aromatic group, optionally respectively substituted by a hydroxyl group, a carboxylic acid group, an amino group or a straight or branched (C1-C4) aliphatic alkyl group;
• R2=an optional group, being a straight or branched (C1-C4) aliphatic alkyl group;
• R3=a straight or branched (C1-C4) aliphatic alkyl group, optionally substituted by one or more carboxylic acid groups, or a straight or branched (C1-C4) aliphatic alkyl amide group;
• or a (C3-C8) cycloalkyl group, optionally substituted by a straight or branched (C1-C4) aliphatic alkyl group or one or more carboxylic acid group.