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US 12,735,444 B2Granted
Chemically cleavable group
AssigneeTagworks Pharmaceuticals B.V.
InventorsMarc Stefan Robillard, Ronny Mathieu Versteegen, Wolter Ten Hoeve, Raffaella Rossin
Life of this patent
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Abstract
Disclosed is the use of the reactive components of the inverse electron-demand Diels Alder reaction for chemical masking and unmasking in vitro. This can be applied in complex chemical reactions and, particularly in the synthesis of biomolecules, e.g. on solid supports. The reactice components are a dienophile, particularly a trans-cyclooctene, and a diene, particularly a tetrazine.
Claims20
A dienophile of Formula (1a):
- wherein A and P each independently are CH2, or CHXD, provided that at least one is CHXD;
- XD is (O—C(O))p-(LD)n-(CA), or O—C(S)-(LD)n-(CA);
- wherein n=0 or 1, wherein p=0 or 1;
- wherein when p=0, LD or CA is bound to the dienophile via O, S, aromatic N or aromatic NH;
- LD is a self-immolative linker consisting of one or more self-immolative units;
- wherein each self-immolative unit is selected from the group consisting of
- wherein the wiggly line indicates a bond to (O—C(O))p or O—C(S) of XD, or to a preceding self-immolative unit;
- wherein the asterisk indicates a bond to CA or to a further self-immolative unit;
- wherein L2 is O, S, NH, or NR with R being alkyl or aryl;
- wherein each L1 is independently H or methyl;
- Y, Z, X, Q each independently are selected from the group consisting of CRa2, C═O, O, and NRb, with at most three of Y, Z, X, and Q being C═O, wherein two R moieties together may form a ring, and with the proviso that no adjacent pairs of atoms are present selected from the group consisting of O—O, and O—NRb;
- wherein each Ra can independently be H, alkyl, aryl, OR′, SR′, S(═O)2R′″, S(═O)2NR′R″, SO3H, PO3H, NO2, CN, CF3, CF2—R′, 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(═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″, or 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 each Rb is independently selected from the group consisting of H, alkyl, aryl, O-aryl, O-alkyl, OH, C(═O)NR′R″ with R′ and R″ each independently being H, aryl or alkyl, and R′CO-alkyl with R′ being H, alkyl, and aryl;
- wherein one Ra or Rb is optionally bound to a construct CB;
- and wherein the self-immolative linker LD, in addition to being bound to CA, is also optionally bound to a construct CB;
- wherein T and G denote H;
- wherein each CA and CB are individually selected from the group consisting of biomolecules, biomolecule-binding moieties, polymers, particles, gels, fluorophores, and radiolabels.
14 more elements
A dienophile of any one of the following formulae:
- wherein the dotted line denotes a bond to the rest of CB and wherein the wavy line indicates a bond to the rest of CA or LD-CA, wherein LD may optionally comprise CB;
- wherein the dotted line denotes a bond to the rest of CB and wherein the wavy line indicates a bond to the rest of CA or LD-CA, wherein LD may optionally comprise CB;
- wherein the dotted line denotes a bond to the rest of CB and wherein the wavy line indicates a bond to the rest of CA or LD-CA, wherein LD may optionally comprise CB;
- wherein LD is a self-immolative linker consisting of one or more self-immolative units;
- wherein each self-immolative unit is selected from the group consisting of
- wherein the wiggly line indicates a bond to (O—C(O))p or O—C(S) of XD, or to a preceding self-immolative unit;
- wherein the asterisk indicates a bond to CA or to a further self-immolative unit;
- wherein L2 is O, S, NH, or NR with R being alkyl or aryl;
- wherein each L1 is independently H or methyl;
- wherein each CA and CB are individually selected from the group consisting of biomolecules, biomolecule-binding moieties, polymers, particles, gels, fluorophores, and radiolabels.
7 more elements
Dependencies are inferred from the claim text.