Abstract: The invention relates to the field of bioconjugation of functional entities (payloads) to targeting agents, in particular biological targeting agents, such as antibody drug conjugates (ADCs), where one or more payload molecules are conjugated to a targeting agent, as for example a monoclonal antibody. More particularly, the present invention relates to novel hydrophilic tetrazine molecules and their preparation, which tetrazines allow a more efficient conjugation of payload molecules to targeting agents, like monoclonal antibodies. The present invention also relates to particular tetrazine intermediates useful for the preparation of correspondingly functionalized payload molecules. The present invention also relates to respective conjugates, in particular bio-conjugates and methods of their preparation. The invention also relates to the use of such conjugates of the present invention for use in medicine, to corresponding pharmaceutical compositions as well as to corresponding diagnostic and analytical kits.

Abstract: The present invention relates to methods for linking tetrazines with dienophiles to establish at least two linkages by sequentially performing at least two cycloaddition reactions. The methods in particular allow establishing multi-labeling strategies. In particular, the invention relates to methods for forming linkages by cycloaddition reactions, wherein the method comprises reacting a first alkyl-substituted tetrazine with a first dienophile comprising a irans-cyclooctenyl group followed by reacting a second tetrazine with a second dienophile comprising a cyclooctynyl group, wherein the reaction of the first tetrazine with the first dienophile proceeds in the presence of the second dienophile.

Abstract: The present invention relates to compounds of formula: and methods for linking tetrazines with dienophiles to establish at least two linkages by sequentially performing at least two cycloaddition reactions. The methods in particular allow establishing multi-labeling strategies. In particular, the invention relates to methods for forming linkages by cycloaddition reactions, wherein the method comprises reacting a first alkyl-substituted tetrazine with a first dienophile comprising a trans-cyclooctenyl group followed by reacting a second tetrazine with a second dienophile comprising a cyclooctynyl group, wherein the reaction of the first tetrazine with the first dienophile proceeds in the presence of the second dienophile.

Abstract: A compound of formula (I), a stereoisomeric form thereof, or a pharmaceutically acceptable salt thereof, wherein the substituents are as defined herein, is provided. The compounds of formula (I) are valuable pharmacologically active compounds and are suitable for the treatment of osteoarthritis. The preparation of the compounds of formula (I), their use as pharmaceuticals, and pharmaceutical compositions including them are also provided.

Abstract: The present invention relates to methods for linking tetrazines with dienophiles to establish at least two linkages by sequentially performing at least two cycloaddition reactions. The methods in particular allow establishing multi-labeling strategies. In particular, the invention relates to methods for forming linkages by cycloaddition reactions, wherein the method comprises reacting a first alkyl-substituted tetrazine with a first dienophile comprising a irans-cyclooctenyl group followed by reacting a second tetrazine with a second dienophile comprising a cyclooctynyl group, wherein the reaction of the first tetrazine with the first dienophile proceeds in the presence of the second dienophile.

Abstract: The present invention relates to unnatural amino acids comprising a cyclooctynyl or trans-cyclooctenyl analog group and having formula (I) or an acid or base addition salt thereof. The invention also relates to the use of said unnatural amino acids, kits and processes for preparation of polypeptides that comprise one or more than one cyclooctynyl or trans-cyclooctenyl analog group. These polypeptides can be covalently modified by in vitro or in vivo reaction with compounds comprising an azide, nitrile oxide, nitrone, diazocarbonyl or 1,2,4,5-tetrazine group.

Abstract: The present invention relates to unnatural amino acids comprising a cyclooctynyl or trans-cyclooctenyl analog group and having formula (I) or an acid or base addition salt thereof. The invention also relates to the use of said unnatural amino acids, kits and processes for preparation of polypeptides that comprise one or more than one cyclooctynyl or trans-cyclooctenyl analog group. These polypeptides can be covalently modified by in vitro or in vivo reaction with compounds comprising an azide, nitrile oxide, nitrone, diazocarbonyl or 1,2,4,5-tetrazine group.

Abstract: The present invention relates to compounds of formula I: or pharmaceutically acceptable salts or tautomers thereof, which are inhibitors of histone deacetylase (HDAC). The compounds of the present invention are useful for treating cellular proliferative diseases, including cancer. Further, the compounds of the present invention are useful for treating neurodegenerative diseases, schizophrenia and stroke among other diseases.

Abstract: The present invention relates to compounds of formula I: or pharmaceutically acceptable salts or tautomers thereof, which are inhibitors of histone deacetylase (HDAC). The compounds of the present invention are useful for treating cellular proliferative diseases, including cancer. Further, the compounds of the present invention are useful for treating neurodegenerative diseases, schizophrenia and stroke among other diseases.

Abstract: Inositol derivatives, compositions comprising inositol derivatives, and methods for using compositions comprising inositol derivatives as agents for activating the secretion of chloride ions and/or treatment of inflammation are described.

Abstract: The present invention relates to crystals of phosphorylated Aurora-A kinase fragment alone and in complex with a ligand, amino acid residues 1-43 of human TPX2. This invention also relates to methods for designing and selecting ligands, in particular allosteric inhibitors of Aurora-A, that bind to the Aurora-A kinase and their use. Further, the present invention relates to certain indene and indole derivatives. The present invention relates to crystals of phosphorylated Aurora-A kinase alone and in complex with a ligand, amino acid residues 1-43 of human TPX2. This invention also relates to methods for designing and selecting ligands that bind to the Aurora-A kinase and their use. Further, the present invention relates to certain indene and indole derivative.

Abstract: The invention refers to compounds according to formula (I), wherein R1 is independently in position 2?, 3?, or in both positions of the A ring and is hydroxyl, linear or branched -0-alkyl, wherein the alkyl group has 1-12 carbon atoms, preferably 3-8, more preferably 4 carbon —O-(alkyl)COOH wherein the alkyl group has 1-12 carbon atoms, preferably 3-8, more preferably 4 carbon atoms, —O-(aryl)COOH, -0-aryl, linear or branched —O—(CH2)m—CH(NH2)—COOH with m=1-6, preferably m=2-4, or any combination thereof; R4 is in position 8?, 10?, or 11? of the D ring of the compound and is H or (CH2)n—CH3 with n=0-6, COOH, CN, or halogen, R5 and R6 independently are ethyl-, methyl-, H, or —(CH2)3 connected to position 8 or 10 of the D ring, and wherein provided that X is O, R2is F, Cl, Br, I, H, CN, —CH?CH-alkyl, —C?—C-alkyl, aryl and R3 is F, Cl, Br, I, CN, —CH?CH-alkyl, —C?C-alkyl, aryl an provided that X is S, R2 and R3 independently are F, Cl, Br, I, H, CN, —CH?CH-alkyl, —C?C-alkyl, aryl.

Abstract: Inositol derivatives, compositions comprising inositol derivatives, and methods for using compositions comprising inositol derivatives as agents for activating the secretion of chloride ions and/or treatment of inflammation are described.

Abstract: Inositol derivatives, compositions comprising inositol derivatives, and methods for using compositions comprising inositol derivatives as agents for inhibiting superoxide anion production are described. The inositol derivatives are obtainable via conventional organic synthesis. The inositol derivatives inhibit superoxide anion produced by neutrophils and macrophages which cause tissue damage.

Abstract: The present invention provides compositions that are cell permeable antagonists of inositol polyphosphates. In addition, the invention provides methods for enhancing chloride ion secretion from a cell by contacting the cells with cell permeable antagonists of inositol polyphosphates. The invention also provides methods for enhancing chloride ion secretion in an individual by administering cell permeable antagonists of inositol polyphosphates to the individual. The invention additionally provides methods for alleviating a sign or symptom associated with cystic fibrosis in an individual by administering a cell permeable antagonist of inositol polyphosphates to the individual. The invention also provides compositions that are cell permeable agonists of inositol polyphosphates. In addition, the invention provides methods for decreasing chloride ion secretion from a cell by contacting the cell with cell permeable agonists of inositol polyphosphates.

Abstract: The present invention provides compositions that are cell permeable antagonists of inositol polyphosphates. In addition, the invention provides methods for enhancing chloride ion secretion from a cell by contacting the cells with cell permeable antagonists of inositol polyphosphates. The invention also provides methods for enhancing chloride ion secretion in an individual by administering cell permeable antagonists of inositol polyphosphates to the individual. The invention additionally provides methods for alleviating a sign or symptom associated with cystic fibrosis in an individual by administering a cell permeable antagonist of inositol polyphosphates to the individual. The invention also provides compositions that are cell permeable agonists of inositol polyphosphates. In addition, the invention provides methods for decreasing chloride ion secretion from a cell by contacting the cell with cell permeable agonists of inositol polyphosphates.

Abstract: Acyloxyalkyl esters of phosphate-containing second messengers which are capable of permeating cell membranes. Once inside the cell, the ester derivatives undergo enzymatic conversion to the biologically active form of the second messenger. The acyloxyalkyl esters have the formula: ##STR1## wherein A.sub.1 to A.sub.6 is H, OH, F or ##STR2## wherein R is an alkyl group having from 2 to 6 carbon atoms and R' is H or CH.sub.3 or R is CH.sub.3 and R' is CH.sub.3 and wherein at least one of A.sub.1 to A.sub.6 is a phosphoester having the formula set forth above.

Abstract: Acyloxyalkyl esters of phosphate-containing second messengers which are capable of permeating cell membranes. Once inside the cell, the ester derivatives undergo enzymatic conversion to the biologically active form of the second messenger. Acyloxyalkyl esters of second messengers, such as cAMP, cGMP, inositol triphosphate and inositol tetraphosphate are disclosed.