Bio-orthogonal drug activation

A prodrug kit comprising a prodrug compound and an activator compound, wherein the prodrug compound comprises a drug moiety DD linked to a trigger moiety TR either directly or via a linker LD, wherein the trigger moiety comprises a dienophile and the activator compound comprises a diene that can react with the dienophile, the dienophile comprising a structure according to formula (1a):

• wherein T and G each independently is H, or a substituent selected from the group consisting of alkyl, F, Cl, Br or I;
• A and P each independently are CRa2 or CRaXD, provided that at least one is CRaXD;
• wherein XD is (O—C(O)p-(LD)n-(DD), S—C(O)-(LD)n-(DD), O—C(S)-(LD)n-(DD), or S—C(S)-(LD)n-(DD), wherein p =0 or 1;
• wherein LD is a self-immolative linker, and n =0 or 1, wherein LD is linear or branched and linked to TR via S, N, NH, or O, wherein these atoms are part of the linker;
• wherein DD is one or more drugs, linked to LD, O—C(O), S—C(O), O—C(S), S—C(S) or CRa via S, N, NH, or O, wherein these atoms are part of the drug;
• and wherein when XD is (O—C(O))p-(LD)n-(DD) and p=0 and LD or DD is bound to TR via N or NH, these N and NH moieties are bound to an aromatic carbon of LD or DD;
• Y, Z, Q, X together form a substituted or unsubstituted four-membered aliphatic moiety;
• wherein Y,Z,X,Q each independently are selected from the group consisting of CRa2, C═CRa2, C═O, with at most one of Y, Z, X, and Q being selected from the group consisting of C═CRa2 and C═O;
• wherein each Ra independently is selected from the group consisting of H, alkyl, aryl, OR′, SR′, S(═O)R′″, S(═O)2R′″, S(═O)2NR′R″, F, Cl, , SO3H, SO4H, NO2, CN, CF3, CF2R′, NR′R″, C(═O)R′, C(═O)OH, C(═O)NR′R″, C(═S)NR′R″, NR′C(═O)—R′″, NR′C(═S)—R′″, NR′C(═OO—R′″, NR′C(═S)O—R′″, NR′C(═O)S—R′″, OC(═O)NR′—R″, SC(═O)NR′—R″, OC(═S)NR′—R″, SC(═S)NW′—R″, NR′C(═S)S—R′″, NR′C(═O)NR″—R″, NR′C(═S)NR″—R″, with each R′ and each R″ independently being H, aryl or alkyl and R′″ independently being aryl or alkyl;
• wherein neither or at least one of the linker LD and the trigger moiety comprises a targeting agent TT or a masking moiety MM;
• wherein TT is an antibody, antibody fragment, protein, peptide, peptide mimetic, polymer, carbohydrate, or oligonucleotide targeting agent, and MM is a protein, peptide, polymer, polyethyleneglycol, or carbohydrate masking moiety;
• wherein the drug moiety DD is selected from the group consisting of proteins, oligopeptides, oligonucleotides, oligosaccharides, peptides, peptoids and organic drug compounds;
• wherein the activator comprises a diene selected from the dienes according to Formula (4)
• wherein R1 and R2 each independently are selected from the group consisting of H, alkyl, aryl, NR′C(═O)R″, NR′C(═S)R″, NR′C(═O)OR″, NR′C(═S)OR″, NR′C(═O)SR″, NR′C(═S)SR″, OC(═O)NR′R″, SC(═O)NR′R″, OC(═S)NR′R″, SC(═S)NR′R″, NR′C(═O)NR″R″, NR′C(═S)NR″R″ with each R′ and each R″ independently being H, aryl or alkyl, and R′″ independently being aryl or alkyl;
• wherein A is N;
• B is N;
• X is N;
• and Y is N;
• wherein neither or at least one of the substituents R1 and R2 on the diene is comprised in a binding to a polymer, protein, peptide, carbohydrate, dendrimer, heparin derivative, hyaluronic acid derivative, albumin, albumin-binding moiety, dye moiety, fluorescent moiety, imaging probe, chelate, liposome, polymer particle or polymersome.