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US 11,884,687 B2Granted
Boronated multifunctional targeting drug conjugates, their uses and methods for their preparation
AssigneeHovione Scientia Limited
InventorsPedro Gois, Fabio Santos
Life of this patent
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Abstract
Tri-component multi-functional boronated complexes (B-complexes), featuring reversible covalent bonds, are described, which incorporate a drug; a water-soluble moiety (e.g. polyethylene glycol (PEG) chains, cyclodextrins); and a targeting unit. A B-complex core was assembled in one step, and proved to be stable in different biocompatible conditions, such as human plasma, though reversible for example in the presence of glutathione (GSH). This platform enabled the modular construction of the multifunctional conjugates exhibiting high selectivity towards, for example, folate-receptor-positive MDA-MB-231 cancer cells, having an IC50 in the low nanomolar range.
Claims21
A multifunctional compound comprising a tripodal boranated core, wherein the multifunctional compound further comprises:
- (a) at least one therapeutically useful cargo molecule, or a residue thereof;
- (b) at least one water-soluble moiety or a residue of a water-soluble molecule;
- and at least one of components (c) or (d), wherein
- (c) is at least one functionalizing moiety capable of being post-functionalised with a targeting unit or a residue of a targeting molecule;
- and
- (d) is at least one targeting unit or a residue of a targeting molecule;
- in which any residue of a molecule is such that, on breaking at least one covalent bond of the multifunctional compound, the complete molecule is released;
- and
- wherein the tripodal boronated core is as defined in the general formula:
- wherein:
- R1 represents H, Cn=1-6 alkyl, alkene or alkyne which can be straight, branched or cyclic and optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulphur;
- formyl or Cn=2-6 alkanoyl;
- or Ar, CH2Ar or CH2CH2Ar, in which the Ar group may be a phenyl, a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p- positions, a naphthyl, a heterocyclic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen or sulphur;
- R2 to R5 represents H, Cn=1-6 alkyl, alkene or alkyne which can be straight, branched or cyclic and optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulphur;
- formyl or Cn=2-6 alkanoyl;
- amide;
- ester;
- Ar, CH2Ar or CH2CH2Ar in which the Ar group may be a phenyl, a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p- positions, a naphthyl, a heterocyclic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen or sulphur, OH, OCH3, OCH2CH3, OCHCH3CH3, OCH2CHCH3CH3, OPh, CCH, CCPh, CN, COOH, NH2, CONHR′ NHR′ or NR′R″ in which the R′ and R″ groups may be optionally a phenyl or a substituted phenyl, a 5 or 6 member azacyclic ring, Cn=1-6 alkyl which optionally may incorporate one further heteroatom selected from oxygen, sulphur or nitrogen;
- R6 to R9 represents H, Cn=1-6 alkyl, alkene or alkyne which can be straight, branched or cyclic and optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulphur;
- formyl or Cn=2-6 alkanoyl;
- amide;
- ester;
- Ar, CH2Ar or CH2CH2Ar in which the Ar group may be a phenyl, a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p- positions, a naphthyl, a heterocyclic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen or sulphur, OH, OCH3, OCH2CH3, OCHCH3CH3, OCH2CHCH3CH3, OPh, CCH, CCPh, CN, COOH, NH2, CONHR′ NHR′ or NR′R″ in which the R′ and R″ groups may be optionally a phenyl, a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p- positions, a 5 or 6 member azacyclic ring, Cn=1-6 alkyl which optionally may incorporate one further heteroatom selected from oxygen, sulphur or nitrogen;
- R10 represents H, Cn=1-6 alkyl, alkene or alkyne which can be straight, branched or cyclic and optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulphur;
- a vinyl group of the general formula CH═CHR′ in which the R′ represents a H, Cn=1-6 alkyl, alkene or alkyne which can be straight, branched or cyclic and optionally contain one or more heteroatom selected from nitrogen, oxygen or sulphur, a phenyl or a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p-positions, a naphthyl, a monocyclic or bicyclic heterocyclic ring comprising at least one ring heteroatom selected from nitrogen, oxygen or sulphur;
- a phenyl or a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p- positions;
- a naphthyl;
- or a monocyclic or bicyclic heterocyclic ring comprising at least one ring heteroatom selected from nitrogen, oxygen or sulphur;
- and
- X and Y each independently represent a heteroatom selected from oxygen or nitrogen
- wherein the at least one therapeutically useful cargo molecule, or a residue thereof comprises an API selected from anti-cancer agents;
- anti-neurodegeneratives;
- or anti-inflammatories;
- and/or an agent selected from chalcone, adamantylamine, or peptides.
31 more elements
A multifunctional compound comprising a tripodal boranated core, wherein the multifunctional compound further comprises:
- (a) at least one therapeutically useful cargo molecule, or a residue thereof;
- (b) at least one water-soluble moiety or a residue of a water-soluble molecule;
- and at least one of components (c) or (d), wherein
- (c) is at least one functionalizing moiety capable of being post-functionalised with a targeting unit or a residue of a targeting molecule;
- and
- (d) is at least one targeting unit or a residue of a targeting molecule;
- in which any residue of a molecule is such that, on breaking at least one covalent bond of the multifunctional compound, the complete molecule is released;
- and
- wherein the tripodal boronated core is as defined in the general formula:
- wherein:
- R1 is H, Cn=1-6 alkyl or phenyl;
- R2 is H;
- R3 is a residue of a water-soluble moiety and/or a functionalising moiety and/or a targeting moiety and the residue of a water-soluble moiety and/or a functionalising moiety and/or a targeting moiety is Rx-[—O—(—CH2)2-]3—O— in which Rx is a C1-6 alkyl chain;
- R4 is H or alkoxy;
- R5 and R6 are H;
- R7 is H, or is or includes the residue of a therapeutically useful cargo water-soluble moiety and/or a functionalising moiety and/or a targeting moiety;
- R8 and R9 are both H;
- R10 is phenyl, or the residue of a therapeutically useful cargo or a residue of an API;
- and
- X and/or Y is O.
17 more elements
A multifunctional compound comprising a tripodal boranated core, wherein the multifunctional compound further comprises:
- (a) at least one therapeutically useful cargo molecule, or a residue thereof;
- (b) at least one water-soluble moiety or a residue of a water-soluble molecule;
- and at least one of components (c) or (d), wherein
- (c) is at least one functionalizing moiety capable of being post-functionalised with a targeting unit or a residue of a targeting molecule;
- and
- (d) is at least one targeting unit or a residue of a targeting molecule;
- in which any residue of a molecule is such that, on breaking at least one covalent bond of the multifunctional compound, the complete molecule is released;
- and
- wherein the tripodal boronated core is as defined in the general formula:
- wherein:
- R1 is H, Cn=1-6 alkyl or phenyl;
- R2 is H;
- R3 is H, or is or includes the residue of a water-soluble moiety and/or a functionalising moiety and/or a targeting moiety;
- R4 is H or alkoxy;
- R5 and R6 re H;
- R7 is a residue of a therapeutically useful cargo water-soluble moiety and/or a functionalising moiety and/or a targeting moiety and the residue of a therapeutically useful cargo water-soluble moiety and/or a functionalising moiety and/or a targeting moiety is Cn=1-6 alkyl amide terminating in either an azide (N3) group or a folate moiety;
- R8 and R9 are both H;
- R10 is phenyl, or the residue of a therapeutically useful cargo or a residue of an API;
- and
- X and/or Y is O.
17 more elements
A multifunctional compound comprising a tripodal boranated core, wherein the multifunctional compound further comprises:
- (a) at least one therapeutically useful cargo molecule, or a residue thereof;
- (b) at least one water-soluble moiety or a residue of a water-soluble molecule;
- and at least one of components (c) or (d), wherein
- (c) is at least one functionalizing moiety capable of being post-functionalised with a targeting unit or a residue of a targeting molecule;
- and
- (d) is at least one targeting unit or a residue of a targeting molecule;
- in which any residue of a molecule is such that, on breaking at least one covalent bond of the multifunctional compound, the complete molecule is released;
- and
- wherein the tripodal boronated core is as defined in the general formula:
- wherein:
- R1 is H, Cn=1-6 alkyl or phenyl;
- R2 is H;
- R3 is H, or is or includes the residue of a water-soluble moiety and/or a functionalising moiety and/or a targeting moiety;
- R4 is H or alkoxy;
- R5 and R6 are H;
- R7 is H, or is or includes the residue of a therapeutically useful cargo water-soluble moiety and/or a functionalising moiety and/or a targeting moiety;
- R8 and R9 are both H;
- R10 is a residue of an API and the residue of an API is bortezomib, SN38, chalcone or adamantylamine;
- and
- X and/or Y is O.
17 more elements
Dependencies are inferred from the claim text.