Bio-orthogonal drug activation

A prodrug kit comprising a prodrug compound and an activator compound, wherein the prodrug compound comprises one or more drug moieties DD linked to a trigger moiety TR via a linker LD, according to Formula 1(a), wherein the trigger moiety comprises a dienophile and the activator comprises a diene that reacts with the dienophile to release the drug moieties from the prodrug molecule, wherein the dienophile comprises a trans-cyclooctene ring;

• wherein the dienophile comprises a structure according to formula (1a)
• wherein A and P are independently CRa2 or CRaXD, provided that at least one is CRaXD, wherein XD is O—C(O)-(LD)n-(DD), S—C(O)-(LD)n-(DD), O—C(S)-(LD)n-(DD), S—C(S)-(LD)n-(DD), NRd—C(O)-(LD)n-(DD), NRd—C(S)-(LD)n-(DD), C(O)-(LD)n-(DD), C(S)-(LD)n-(DD), wherein LD is a linker and n=0 or 1, DD is the one or more drug moieties;
• wherein LD is selected from
• wherein at least one of the drug DD, the linker LD and the trigger moiety comprises a targeting agent TT or a masking moiety MM.,
• wherein SP is an alkyl, a polyethylene glycol, a peptide or a polylactide spacer, TT is an antibody, antibody fragment, protein or peptide targeting agent, and MM is a protein, peptide, polymer, polyethylene glycol, or carbohydrate masking agent;
• wherein T and G are H or a substituent selected from the group consisting of alkyl, F, Cl, Br, and I;
• wherein Q, X, Z and Y are CRa2 or CRe2,
• wherein Ra is selected from the group consisting of alkyl, aryl, OR′, SR′, S(═O)R′″, S(═O)2R′″, S(═O)2NR′R″, Si—R′″, Si—O—R′″, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, F, Cl, Br, I, N3, SO2H, SO3H, SO4H, PO3H, PO4H, NO, NO2, CN, OCN, SCN, NCO, NCS, CF3, CF2—R′, NR′R″, C(═O)R′, C(═S)R′, C(═O)O—R′, C(═S)O—R′, C(═O)S—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′R″, NR′C(═O)—R′″, NR′C(═S)—R′″, NR′C(═O)O—R′″, NR′C(═S)O—R′″, NR′C(═O)S—R′″, NR′C(═S)S—R′″, 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″, CR′NR″, with each R′ and each R″ independently being H, aryl or alkyl and R′″ independently being aryl or alkyl;
• wherein Re is selected from the group consisting of H, alkyl, aryl, OR′, SR′, S(═O)R′″, S(═O)2R′″, Si—R′″, Si—O—R′″, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, F, Cl, Br, I, N3 SO2H, SO3H, PO3H, NO, NO2, CN, CF3, CF2—R′, C(═O)R′, C(═S)R′, C(═O)O—R′, C(═S)O—R′, C(═O)S—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′R″, NR′C(═O)—R′″, NR′C(═S)—R′″, NR′C(═O)O—R′″, NR′C(═S)O—R′″, NR′C(═O)S—R′″, NR′C(═S)S—R′″, NR′C(═O)NR″—R″, NR′C(═S)NR″—R″, CR′NR″, with each R′ and each R″ independently being H, aryl or alkyl and R′″ independently being aryl or alkyl;
• wherein the one or more drug moieties DD are selected from the group of auristatins, maytansines, calichcamicin, duocmmycins, maytansinoids DM1 and DM4, auristatin MMAE, duocarmycin CC1065, camptothecin, irinotecan SN-38, initomycins, bleomycins, taxanes, lexitropsins, pteridines, diynenes, podophyllotoxins, dolastatins, taxols, duocarmycins, methotrexate, methopterin, dichloromethotrexate, 6-mercaptopurinc, cytosine arabinoside, melphalan, leurosine, leurosideine, actinomycin, launombicin, doxorubicin, mitomycin C, mitomycin A, caminomycin, aminopterin, tallysomycin, etoposide, etoposide phosphate, vinblastine, vincristine, vincristine, vindesine, taxotere, retinoic acid, butyric acid, N8-acetyl spermidine, calicheamicin, and esperamicin;
• 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, CF3, CF2—R′, NO, NO2, OR′, SR′, CN, C(═O)R′, C(═S)R′, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, S(═O)R′, S(═O)2R′″, S(═O)2OR′, PO3R′R″, S(═O)2NR′R″, C(═O)O—R′, C(═O)S—R′, C(═S)O—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′R″, NR′R″, 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.