Curcumin conjugates and methods of use thereof
Inventors
Assignees
Augusta University • Augusta University Research Institute Inc
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Publication Number
US-10660967-B2
Publication Date
2020-05-26
Expiration Date
Abstract
Curcumin-based conjugates and methods of use thereof are provided. Pharmaceutical compositions including an effective amount of one or more curcumin conjugates are also provided. In particular embodiments, the compositions are formulated for oral delivery. The conjugates and pharmaceutical compositions thereof can be administered to a subject in need thereof to treat a host of diseases and disorders including but not limited to, cancer, inflammation, and microbial growth.
Core Innovation
The invention relates to curcumin conjugates defined by a general structural formula in which dotted lines indicate that a single or double bond may be present between A and C1, between C1 and C2, and between C2 and C3, as valence permits. The dotted lines also indicate that a single bond or no bond may be present between A and M and between D and Q, with A and D as oxygen atoms and C1, C2, and C3 as carbon atoms.
The curcumin conjugates further define substituents R2 and R3 as one or more amino acids or salts thereof, nucleic acids, lipids, polysaccharides, polymers, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, or other organic groups containing between C1 and C10 carbon atoms, inclusive. The substituents R1 and R4 are carboxybenzyl (Cbz) or fluorenylmethyloxycarbonyl (FMOC), and L1 and L2 are independently absent, substituted or unsubstituted groups containing between C1 and C10 carbon atoms inclusive, or a combination thereof.
The invention also encompasses pharmaceutically acceptable salt(s), polymorph(s), solvent(s), hydrate(s), crystal forms, and/or enantiomer(s) thereof. In addition, the document describes pharmaceutical compositions comprising selected curcumin conjugates from an explicitly enumerated group of specific bis(2-methoxy-4,1-phenylene) conjugates, including benzyloxycarbonyl and fluorenylmethyloxycarbonyl amino-propanoate or aminoacetate substituents, stereochemical forms such as (2S,2′S) and (2R,2′R), and side-chain substitution including methylthio.
Claims Coverage
The independent claim coverage centers on three inventive features: a curcumin conjugate defined by a general formula with valence-permitted bond variation and broad substituent classes, specified R1/R4 protection groups limited to Cbz or FMOC, and a pharmaceutical composition containing an explicitly enumerated set of curcumin conjugates with defined stereochemistry and side-chain substitution.
General formula-defined curcumin conjugates with valence-permitted bond possibilities
A curcumin conjugate of a general formula in which dotted lines indicate that a single or double bond may be present between A and C1, between C1 and C2, and between C2 and C3, as valence permits, and that a single bond or no bond may be present between A and M and between D and Q, with A and D as oxygen atoms and C1, C2, and C3 as carbon atoms.
Curcumin conjugates with broad substituent options and Cbz or FMOC at R1/R4
The curcumin conjugate of the general formula where R2 and R3 can be one or more amino acids or salts thereof, nucleic acids, lipids, polysaccharides, polymers, or other specified organic groups containing between C1 and C10 carbon atoms inclusive, and where R1 and R4 can be carboxybenzyl (Cbz) or fluorenylmethyloxycarbonyl (FMOC), with L1 and L2 independently absent or selected from specified groups.
Pharmaceutical composition containing explicitly enumerated curcumin conjugates
A pharmaceutical composition comprising a curcumin conjugate selected from a group consisting of specified (1E,6E)-3,5-dioxohepta-1,6-diene-1,7-diyl bis(2-methoxy-4,1-phenylene) conjugates, including benzyloxycarbonyl and fluorenylmethyloxycarbonyl amino-propanoate or aminoacetate derivatives, stereochemical forms such as (2S,2′S) and (2R,2′R), and side-chain substitution including methylthio, together with pharmaceutically acceptable salt(s), polymorph(s), solvent(s), hydrate(s), crystal forms, and/or enantiomer(s) thereof.
The independent claims combine a general curcumin-conjugate formula with configurable bond states and substituent classes, defined Cbz or FMOC protection at R1/R4, and a pharmaceutical composition claim limited to an explicitly enumerated set of curcumin conjugates with stereochemical and side-chain variations.
Stated Advantages
Improved anti-inflammatory potency in acute carrageenan-induced paw edema in rats, reported relative to indomethacin and ibuprofen.
Chiral integrity of the conjugates is confirmed by optical rotation and chiral HPLC.
Structure-dependent properties are reported through theoretical and experimental LogP and LogS values that depend on protecting groups and amino acids.
Documented Applications
Anti-inflammatory testing in rats using acute carrageenan-induced paw edema, with certain curcumin conjugates identified as having anti-inflammatory potency relative to indomethacin and ibuprofen.
Pharmaceutical compositions containing the enumerated curcumin conjugates are contemplated for therapeutic use.
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