Novel citicoline derivatives

Abstract

Novel citicoline derivatives are disclosed, including ddh-citicoline, comprising a choline moiety, attached to an organic functional group linking the nucleoside to the choline moiety, including prodrug modifications, wherein choline-conjugated pharmacophores / cargo could be delivered through the gut via promiscuous choline transporters. The invention further provides a nutraceutical or pharmaceutical composition comprising an inventive compound, and a pharmaceutically-acceptable excipient, preferably in a pharmaceutically-acceptable unit dosage.

Description

[0001] Novel Citicoline Derivatives

[0002]

[0001] Cross-references to related applications

[0003]

[0002] This application claims priority to U.S. Prov. App. No. 63 / 515,336, filed Jul 24, 2024, the disclosures of which are hereby incorporated by reference in its entirety for all purposes.

[0004]

[0003] Introduction

[0005]

[0004] Cytidine diphosphate choline (citicoline) is a nootropic nutraceutical with clinically demonstrated therapeutic benefits for a wide range of indications. Its well-documented therapeutic benefits and exceptional safety profile make citicoline a highly utilized supplement generating $300 million in business per year.

[0006]

[0005] Citicoline is a composed of two functional units, cytidine diphosphate (CDP) and choline. Upon oral administration, citicoline is broken down by first pass metabolism into CDP and choline. Both metabolites are then distributed throughout the body. Choline is largely regarded as the limiting therapeutic agent, as the human body does not biosynthesize enough choline to meet its metabolic demand.

[0007]

[0006] 3 ’ -Deoxy-3 ’ ,4’ -didehydro-cytidine triphosphate (ddhCTP) is a recently discovered nucleotide that offers a wide range of potential health benefits due to its immunomodulatory physiological effect on mammalian systems. ddhC has been shown to modulate host physiology in ways that could be used to treat a wide range of diseases.

[0008]

[0007] Relevant Literature includes: Wood et al. J. Org. Chem. 2021, 86, 13, 8843-8850; Wood et al. Tetrahedron Letters, 119, 12 April 2023, 154423.

[0009]

[0008] Summary of the Invention

[0010]

[0009] The invention provides novel citicoline derivatives, including ddh-citicoline and derivatives, as prodrugs for neutraceutical, pharmaceutical or therapeutic compositions, and related methods of use.

[0011]

[0010] In an aspect the invention provides a compound of the following formula, or salt, hydrate or stereoisomer thereof: [Oil] wherein:

[0012]

[0012] X is O, S, Se or C;

[0013]

[0013] R1 is a nucleobase, including ddh versions thereof, including:

[0014]

[0014] a natural nucleobase: e.g. adenine (A), thymine (T), cytosine (C), guanine (G), Uracil (U), N6-methyladenine (6mA), N6-dimethyladenine (6-DMA), N6,N6-dimethyladenine (6,6- DMA), N6-hydroxymethyladenine (6-hmA), N6-formyladenine (6-FA), N6- threonylaminomethyladenine (6-TAM), 5 -methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), 5-carboxylcytosine (5caC), 5,6-dihydroxycytosine (dhC), 5,6- dihydroxy-5-methylcytosine (dhmC), 5,6-dihydroxymethyl-5-methylcytosine (dhmC), N4- methylcytosine (4mC), N4-hydroxymethylcytosine (4hmC), N4-formylcytosine (4fC), N4- carboxylcytosine (4caC), N4-Acetylcytosine (4acC), N4-propionylcytosine (4pcC), 7-, methylguanine (7mG), 7,8-dihydro-8-oxoguanine (8-oxoG), 2-aminoadenine (2AA), 2,6- diaminopurine (DAP), 2-amino-6-methylaminopurine (m2A), 2,2'-anhydroribonucleoside (AAR), inosine (I), xanthine (X), hypoxanthine (Hx), queuosine (Q), archaeosine (G+), oxythiamine (OT), isoguanine (IsoG), 6-hydroxyaminopurine (HAP), 4-amino-6- hydroxypyrimidine (pHAP), 2-Amino-6-hydroxypurine (xHAP), 5-chlorouracil, 6-chlorouracil, 2-chloroadenine, 6-chloroguanine, and 5 -bromouracil;

[0015]

[0015] a non-natural nucleobase: e.g. N1 -methylpseudouridine, ddhG, ddhA, ddhU, 5-ethynyl- 2 ’-deoxyuridine, biotin- 11 -deoxyuridine, pseudouridine, 5-methylcytidine, aminoallyl-uridine- X-Cy5, Cy5-uridine, fluorescein- 12-uridine, aminoallyl -uridine-X-cy3, Cy3-uridine, fluorescein- 12-deoxyuridine, cyanin 7-AA-uridine, cyanin 5-AA-cytidine, cyanine 3-AA- cytidine, cyanine 5-deoxyuridine, cyanine 5-deoxycytidine, cyanine 3-deoxycytidine, biotin- 16- deoxy guanosine, desthiobiotin-16-uridine, desthiobiotin- 6- deoxycytidine, biotin- 16- uridine, N4-biotin-OBEA-deoxycitidine, biotin- 16-cytidine, biotin- 16-deoxycytidine, biotin- 16- deoxyuridine, 3 ’-azido-cytidine, 3’-amino-deoxythymidine, 3 ’-amino-deoxyguanosine, 3’- amino-deoxyadenosine, 3’-amino-deoxycytidine, 3 ’-azido-deoxy thymidine, 3 ’-azidodeoxyguanosine, 3’-azido-deoxyadenosine, 3’-azido-deoxycytidine, 2’ -deoxythymidine, 2’- deoxyadenosine, 2’-deoxyuridine, 2’ -deoxyguanosine, 2’-deoxcytidine, 5-methyl-uridine, 2’-O- (2-nitrobenzyl)-inosine, 2’-O-(2-nitrobenzyl)-adenosine, 7-Deaza-7-Propargylamino- deoxyguanosine, deaza-7-Propargylamino-deoxyadenosine, 5-formyl-uridine, 5-formyl- deoxyuridine, 5-carboxy-uridine, 5-carboxy-deoxyuridine, 5-indolyl-AA-uridine, 5-indolyl-AA- deoxyuridine, 5-formyl-cytidine, 5-formyl-deoxycytidine, 5-carboxy-cytidine, 5-carboxy- deoxycytidine, 5-propargylamino-deoxyuridine, 5-propargylamino-uridine, 5-propargylamino- deoxycytidine, 5 -propargylamino-cytidine, 5-hme-deoxycytidine, 5-hme-cytidine, 5-hmd- deoxyuridine, 5-hmd-uridine, 2’deoxyzebularine, N4-methyl-cytidine, N4-methyl-deoxycitidine, 8-chloro-adenosine, 8-chloro-deoxyadenosine, 6-thio-guanosine, 6-thio-deoxyguanosine, 6-aza- deoxyuridine, 6-aza-uridine, 2-thio-cytidine, 2-thio-deoxycytidine, 4-thio-thymidine, 4-thio- deoxythymidine, 5-hydroxy-deoxycytidine, 5-hydroxy-cytidine, 2-deoxy-P-nucleoside, P- nucleoside, 2-thio-deoxythymidine, 8-oxo-deoxyguanosine, 8-oxo-guanosine, 8-oxo- deoxyadenosine, 8-oxo-adenosine, 5-nitro-l-indolyl-deoxyribose, 5-nitro-l-indolyl-ribose, N2- methyl-deoxyguanosine, N2-methyl-guanosine, O6-methyl-deoxyguanosine, O6-methyl- guanosine, 5-methyl-deoxycytidine, 5-methyl-cytidine, N6-methyl-deoxyadenosine, N6-methyl- adenosine, 5-iodo-deoxyuridine, 5-iodo-uridine, 5-iodo-cytidine, 5-iodo-deoxycytidine, 5- fluoro-deoxyuridine, 5 -fluoro-uridine, 5-propynyl-deoxyuridine, 5-propynyl-uridine, 5- propynyl-deoxycytidine, 5-propynyl-cytidine, deoxyinosine, inosine, 7-deaza-deoxyguanosine, 7-deaza-guanosine, 7-deaza-deoxyadenosine, 7 -deaza- adenosine, 6-chloro-purine-deoxyribose, 6-chloro-purine-ribose, 5-bromo-deoxyuridine, 5-bromo-uridine, 5-bromo-deoxycytidine, 5- bromo-cytidine, 2-aminopurine-deoxyribose, 2-aminopurine-ribose, 2-amino-deoxyadenosine, 2-amino-adenosine, 2-amino-6-chloro-purine-deoxyribose, 2-amino-6-chloro-purine-ribose, 2’- O-methyl-N6-methyl-adenosine, Nl-propyl-pseudouridine, Nl -propyl-pseudo-deoxyuridine, N 1 -methyl-2’ -methylpseudo-uridine, N 1 -ethylpseudo-uridine, N 1 -ethylpseudo-deoxyuridine, ara-guanosine, iso-guanosine, iso-deoxyguanosine, 8-oxo-adenosine, 8-oxo-deoxyadenosine, thieno-cytidine, thieno-deoxycytidine, 5-carboxymethylester-uridine, 5-carboxymethylester- deoxyuridine, thieno-uridine, thieno-deoxyuridine, 5-methoxy-cytidine, 5-methoxy- deoxycytidine, 5-methoxy-uridine, 5-methoxy-deoxyuridine, 5 -hydroxy-uridine, 5-hydroxy- deoxyuridine, 5-carboxy-uridine, 5-carboxy-deoxyuridine, 5-formyl-uridine, 5-formyl- deoxyuridine, 5-hydroxy-cytidine, 5-hydroxy-deoxycytidine, thieno-guanosine, thieno- deoxyguanosine, 5-hme-cytidine, 5-hme-deoxycytidine, 5-hrne -uridine, 5-hme-deoxyuridine, 5- formyl-cytidine, 5-formyl-deoxycytidine, 5 -carboxy-cytidine, 5’-carboxy-deoxycytidine, N6- methyl-amino-adenosine, N6-methyl-amino-deoxyadenosine, 5,6-dihydro-5-methyluridine, 5,6- dihydro-5-methyl-deoxyuridine, N1 -methylpseudo-uridine, N 1 -methylpseudo-deoxyuridine, N4-methyl-cytidine, N4-methyl-deoxycytidine, pseudoisocytidine, pseudoisodeoxycytidine, 2- aminopurine -ribose, 2-aminopurine-deoxyribose, 8-oxo-guanosine, 8-oxo-deoxyguanosine, aminoallyl-cytidine, aminoallyl-deoxycytidine, 2’-amino-deoxyguanosine, 2’-amino-guanosine, 2 ’-azido-deoxy guanosine, 2’-azido-guanosine, 7-deaza-adenosine, 7-deaza-deoxyadenosine, 3’- O-methyl-uridine, 3’-O-methyl-deoxyuridine, 3’-O-methyl-cytidine, 3’-O-methyl- deoxycytidine, 3’-O-methyl-guanosine, 3’-O-methyl-deoxyguanosine, 3’-O-methyl-adenosine, 3’-O-methyl-deoxyadenosine, 3’-O-methyl-adenosine, 3’-O-methyl-deoxyadenosine, 2’-fluoro- deoxythymidine, 2’-fluoro-thymidine, 5-bromo-uridine, 5-bromo-deoxyuridine, 5-bromo- cytidine, 5-bromo-deoxycytidine, 8-azido-adenosine, 8-azido-deoxyadenosine, ara-adenosine, 2’-amino-deoxyadenosine, 2’ -amino-adenosine, 2’-azido-deoxyadenosine, 2’-azido-adenosine, 7-deaza-guanosine, 7-deaza-deoxy guanosine, 2’-O-Methyl-5-methyl-uridine, Nl-methyl- adenosine, Nl-methyl-deoxyadenosine, 2’-O-methyl-pseudouridine, 2’-O-methyl-2-amino- adenosine, N1 -methylguanosine, Nl-methyl-deoxy guanosine, 6- Aza-uridine, 6-Aza- deoxyuridine, 6- Aza-cytidine, 6-aza-deoxycytidine, 2-thio-cytidine, 2-thio-deoxycytidine, 5,6- dihydro-uridine, 5,6-dihydro-deoxyuridine, ara-uridine, ara-cytidine, 2-thio-uridine, 2-thio- deoxyuridine, O6-methyl-guanosine, O6-methyl-deoxyguanosine, 2’-azido-deoxyuridine, 2’- azido-deoxycytidine, 2’-amino-deoxyuridine, 2’-amino-deoxycytidine, 4-thio-uridine, 5-methyl- uridine, xanthosine, puromycin, 2’-O-meythyl-inosine, inosine, 2’-O-methyl-uridine, 2’-O- methyl-guanosine, 2’-O-methyl-cytidine, 2’-O-methyl-adenosine, N6-methyl-adenosine, 5-iodo- uridine, 5-iodo-cytidine, 2’-fluoro-deoxyuridine, 2 ’-fluoro-deoxy guanosine, 2’-fluoro- deoxycytidine, 2’-fluoro-deoxyadenosine, 6-chloro-purine-ribose, 8-aza-adenosine, 2-amino-6- chloro-purine-ribose, Cy3-deoxyuridine, 2-amino-adenosine, digoxigenin- 11 -dideoxyuridine, digoxigenin- 11 -uridine, digoxigenin- 11 -deoxyuridine, digoxigenin- 11 -dideoxyadenosine, digoxigenin- 11 -adenosine, digoxigenin- 1 1-deoxyadenosine, digoxigenin-1 1-dideoxyguanosine, digoxigenin- 11 -guanosine, digoxigenin-11 -deoxyguanosine, digoxigenin-11-dideoxycytidine, digoxigenin- 11 -cytidine, digoxigenin- 11 -deoxycytidine, aminoallyl-uridine, aminoallyldeoxyuridine,

[0016]

[0016] R2 is an organic functional group linking the nucleoside and choline moieties, including prodrug modifications to increase pharmacokinetic profile, and including:

[0017]

[0017] a hydrolyzable linker: e.g. POM, SATE, DTE, cycloSai, HepDirect, ProTide, HDP, aminoacid phosphoramidite, methylaryl haloalkylamidite;

[0018]

[0018] a nonhydrolyzable linker: e.g. methylene bridge, boranophosphate modification, thiophosphate modification, methylphosphonate modification, methylenediphosphonate modification, boranodiphosphate modification, thiomethylenediphosphate modification, methylthiophosphate modification, methylenecarbonyl modification, phosphorothioate modification, phosphoramidate modification, sulfamate modification, phosphoroamidate modification, sulfonate modification, phosphorodithioate modification, phosphoroselenoate modification, phosphorodiselenoate modification, phosphoramidate triester modification, phosphorofluoridate modification

[0019]

[0019] R3 is hydrogen, thiol, halide, or C1-C4 alkyl;

[0020]

[0020] R4 is hydrogen or C 1 -C4 alkyl.

[0021]

[0021] In embodiments:

[0022]

[0022] X is O:

[0023]

[0024]

[0025] R3 is hydrogen:

[0027] the compound comprises any combination of embodiments wherein X is O, R1 is cytosine, R2 is diphosphate, R3 is hydrogen or R4 is hydrogen, such as wherein:

[0025]

[0028] X is O, and R1 is cytosine ,

[0026]

[0029] X is O and R2 is diphosphate,

[0027]

[0030] X is O and R3 is hydrogen,

[0028]

[0031] X is O and R4 is hydrogen,

[0029]

[0032] R1 is cytosine, and R2 is diphosphate,

[0030]

[0033] R1 is cytosine, and R3 is hydrogen,

[0031]

[0034] R1 is cytosine, and R4 is hydrogen,

[0032]

[0035] R2 is diphosphate, R3 is hydrogen,

[0033]

[0036] R2 is diphosphate, R4 is hydrogen,

[0034]

[0037] R3 is hydrogen, R4 is hydrogen,

[0035]

[0038] X is O, R1 is cytosine, R2 is diphosphate

[0036]

[0039] X is O, R1 is cytosine, R2 is diphosphate, R3 is hydrogen and R4 is hydrogen:

[0037]

[0040] the choline moiety is conjugated to a biomolecule as a universal oral drug delivery strategy, such as wherein choline-conjugated pharmacophores / cargo could be delivered through the gut via promiscuous choline transporters.

[0038]

[0041] In aspects the invention provides a nutraceutical or pharmaceutical composition comprising a compound herein, and a pharmaceutically-acceptable excipient, preferably in pharmaceutically-acceptable unit dosage.

[0039]

[0042] In aspects the invention provides a method of providing a neutraceutical, pharmaceutical or therapeutic, comprising administering to a person in need thereof a compound or composition herein.

[0040]

[0043] In aspects the invention provides a method of delivering or improving delivery of a poorly bioavailable small molecule drug across the gut, comprising delivering to the gut of a person in need thereof, a drug-choline conjugate according to the choline conjugation strategy described herein.

[0041]

[0044] The invention encompasses all combinations of the particular embodiments recited herein, as if each combination had been laboriously recited.

[0045] Description of Particular Embodiments of the Invention

[0042]

[0046] Unless contraindicated or noted otherwise, in these descriptions and throughout this specification, the terms “a” and “an” mean one or more, the term “or” means and / or. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein, including citations therein, are hereby incorporated by reference in their entirety for all purposes.

[0047] The invention provides ddh-citicoline and derivatives, and related compositions and method, ddh-citicoline provides a pharmacokinetic profile similar to citicoline. The invention provides compounds including ddhCDP, ddhNDP, and prodrug formulations of ddhNDPs.

[0043]

[0048] Oral administration of ddh-citicoline derivatives results in hydrolysis of the prodrug into choline and the ddhCDP derivative.

[0044]

[0049] The invention provides use of the compounds and compositions to elicit therapeutic benefits of citicholine and that of ddhC. ddhCTP is well-tolerated in mammalian systems, exhibiting no apparent toxicity. In embodiments the compounds and compositions are used to treat a citicholine indication selected from ocular degenerative disorders (Glaucoma and AMD), Stroke and traumatic brain injury recovery, neurodegenerative disorder treatment (Alzheimer’s and Parkinson’s), substance abuse disorder treatment, cardiovascular health, and treatment for fatty liver disease. In embodiments the compounds and compositions are used to treat a ddhC indication selected from inflammatory, metabolic, and infectious diseases, including but not limited to cancer, viral and bacterial infection, autoimmune disorders, cardiovascular disease, diabetes, obesity, neurological disorders and chronic pain. In embodiments the compounds and compositions are used to directly inhibit viral infection by acting as a chain terminator. Targetable viruses include HBV, HCV, HIV, ZIKV, DENV, Norovirus, CVB4, EVA71, rotavirus, IAV, Yellow fever virus, EBV, HSV, and filoviruses. In embodiments the compounds and compositions are used to treat bacterial and helminthic pathogens.

[0045]

[0050] Synthesis and functional activity assaying / testing of the disclosed compounds and composition may be performed according to published methods for making and testing citicholine and ddhCTP. For example ddhCTP may be prepared according to the synthesis outlined in Wood et al. J. Org. Chem. 2021, 86, 13, 8843-8850 (supra), to ddhCMP and then performing the reaction described in Example 2 of EP2820028A1 (WO2013128393A1), but with ddhCMP instead of cytidine 5 '-monophosphate; in particular, to the solution of cytidine 5'- monophospahate (5'-CMP) (100 gm) in methanol (750 ml), solution of morpholine (75 gm) and DCC (100 gm) in methanol was added at room temperature. The temperature of the reaction was raised to 50-55°C for a time period of 3-7 hrs followed by cooling the reaction mass and filtered to get morpholidiate cytidine 5'- monophospahate in mother liquor. To this, solution of calcium phosphoryl choline chloride (200 gm) in methanol was added and the temperature of reaction mass was raised to 50-55°C and maintained at pH of 3.5 by methanolic HC1. The reaction mass was cooled and filtered to get crude Citicoline by adding IPA. Further, morpholidiate salt of oxalic acid (138.3 gm) was added to the solution of crude citicoline in methanol at 30-35 °C followed by the addition of IPA to get the precipitated Citicoline, which is further treated with activated charcoal in water followed by filtration. To filtrate containing purified Citicoline, aqueous solution of sodium hydroxide was added at room temperature followed by addition of ethanol and the temperature of reaction mass was raised to 50-55°C. The precipitated product was filtered and dried where the purity of citicoline sodium is > 99% measured by HPLC (265 gm).

Claims

CLAIMS1 . A compound of the following formula, or salt, hydrate or stereoisomer thereof:wherein:X is O, S, Se or C;R1 is a nucleobase, including ddh versions thereof;R2 is an organic functional group linking the nucleoside and choline moieties, including prodrug modifications to increase pharmacokinetic profile;R3 is hydrogen, thiol, halide, or C1-C4 alkyl; andR4 is hydrogen or C1-C4 alkyl.

2. The compound of claim 1, wherein R1 is a natural nucleobase selected from: adenine (A), thymine (T), cytosine (C), guanine (G), Uracil (U), N6-methyladenine (6mA), N6- dimethyladenine (6-DMA), N6,N6-dimethyladenine (6,6-DMA), N6-hydroxymethyladenine (6- hmA), N6-formyladenine (6-FA), N6-threonylaminomethyladenine (6-TAM), 5-methylcytosine (5mC), 5 -hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), 5-carboxylcytosine (5caC), 5,6-dihydroxycytosine (dhC), 5,6-dihydroxy-5-methylcytosine (dhmC), 5,6-dihydroxymethyl-5- methylcytosine (dhmC), N4-methylcytosine (4mC), N4-hydroxymethylcytosine (4hmC), N4- formylcytosine (4fC), N4-carboxylcytosine (4caC), N4-Acetylcytosine (4acC), N4- propionylcytosine (4pcC), 7-, methylguanine (7mG), 7,8-dihydro-8-oxoguanine (8-oxoG), 2- aminoadenine (2AA), 2,6-diaminopurine (DAP), 2-amino-6-methylaminopurine (m2A), 2,2'- anhydroribonucleoside (AAR), inosine (I), xanthine (X), hypoxanthine (Hx), queuosine (Q), archaeosine (G+), oxythiamine (OT), isoguanine (IsoG), 6-hydroxyaminopurine (HAP), 4- amino-6-hydroxypyrimidine (pHAP), 2-Amino-6-hydroxypurine (xHAP), 5-chlorouracil, 6- chlorouracil, 2-chloroadenine, 6-chloroguanine, and 5-bromouracil, including ddh versions thereof.

3. The compound of claim 1, wherein R1 is a non-natural nucleobase selected from: Nl- methylpseudouridine, ddhG, ddhA, ddhU, 5-ethynyl-2’ -deoxyuridine, biotin- 11 -deoxyuridine, pseudouridine, 5 -methylcytidine, aminoallyl-uridine-X-Cy5, Cy5-uridine, fluorescein- 12-uridine, aminoallyl-uridine-X-cy3, Cy3-uridine, fluorescein- 12-deoxyuridine, cyanin 7-AA- uridine, cyanin 5-AA-cytidine, cyanine 3-AA-cytidine, cyanine 5-deoxyuridine, cyanine 5- deoxycytidine, cyanine 3-deoxycytidine, biotin- 16- deoxy guanosine, desthiobiotin-16-uridine, desthiobiotin- 6- deoxycytidine, biotin- 16- uridine, N4-biotin-OBEA-deoxycitidine, biotin- 16- cytidine, biotin- 16-deoxycytidine, biotin- 16-deoxyuridine, 3 ’-azido-cytidine, 3 ’-aminodeoxythymidine, 3 ’-amino-deoxyguanosine, 3’-amino-deoxyadenosine, 3’-amino- deoxycytidine, 3’-azido-deoxythymidine, 3 ’-azido-deoxyguanosine, 3’-azido-deoxyadenosine, 3’-azido-deoxycytidine, 2’ -deoxythymidine, 2’-deoxyadenosine, 2’-deoxyuridine, 2’- deoxyguanosine, 2’-deoxcytidine, 5-methyl-uridine, 2’-O-(2-nitrobenzyl)-inosine, 2’-O-(2- nitrobenzyl)-adenosine, 7-Deaza-7-Propargylamino-deoxyguanosine, deaza-7-Propargylamino- deoxyadenosine, 5-formyl-uridine, 5-formyl-deoxyuridine, 5 -carboxy-uridine, 5-carboxy- deoxyuridine, 5-indolyl-AA-uridine, 5-indolyl-AA-deoxyuridine, 5-formyl-cytidine, 5-formyl- deoxycytidine, 5 -carboxy-cytidine, 5-carboxy-deoxycytidine, 5 -propargylamino-deoxy uridine, 5 -propargylamino-uridine, 5-propargylamino-deoxycytidine, 5 -propargylamino-cytidine, 5-hme- deoxycytidine, 5-hme-cytidine, 5-hmd-deoxyuridine, 5-hmd-uridine, 2’deoxyzebularine, N4- methyl-cytidine, N4-methyl-deoxycitidine, 8-chloro-adenosine, 8-chloro-deoxyadenosine, 6- thio-guanosine, 6-thio-deoxyguanosine, 6-aza-deoxyuridine, 6-aza-uridine, 2-thio-cytidine, 2- thio-deoxycytidine, 4-thio-thymidine, 4-thio-deoxythymidine, 5-hydroxy-deoxycytidine, 5- hydroxy-cytidine, 2-deoxy-P-nucleoside, P-nucleoside, 2-thio-deoxythymidine, 8-oxo- deoxyguanosine, 8-oxo-guanosine, 8-oxo-deoxyadenosine, 8-oxo-adenosine, 5-nitro-l-indolyl- deoxyribose, 5-nitro-l-indolyl-ribose, N2-methyl -deoxyguanosine, N2-methyl-guanosine, 06- methyl-deoxyguanosine, O6-methyl-guanosine, 5-methyl-deoxycytidine, 5-methyl-cytidine, N6- methyl-deoxyadenosine, N6-methyl- adenosine, 5-iodo-deoxyuridine, 5-iodo-uridine, 5-iodo- cytidine, 5-iodo-deoxycytidine, 5-fluoro-deoxyuridine, 5 -fluoro-uridine, 5-propynyl- deoxyuridine, 5-propynyl-uridine, 5-propynyl-deoxycytidine, 5-propynyl-cytidine, deoxyinosine, inosine, 7-deaza-deoxyguanosine, 7-deaza-guanosine, 7-deaza-deoxyadenosine, 7-deaza-adenosine, 6-chloro-purine-deoxyribose, 6-chloro-purine-ribose, 5-bromo-deoxyuridine, 5 -bromo-uridine, 5-bromo-deoxycytidine, 5-bromo-cytidine, 2-aminopurine-deoxyribose, 2- aminopurine -ribose, 2-amino-deoxyadenosine, 2-amino-adenosine, 2-amino-6-chloro-purine- deoxyribose, 2-amino-6-chloro-purine-ribose, 2’-O-methyl-N6-methyl-adenosine, N1 -propylpseudouridine, N 1 -propyl-pseudo-deoxyuridine, Nl-methyl-2’ -methylpseudo-uridine, Nl- ethylpseudo-uridine, Nl-ethylpseudo-deoxyuridine, ara-guanosine, iso-guanosine, isodeoxyguanosine, 8-oxo-adenosine, 8-oxo-deoxyadenosine, thieno-cytidine, thieno- deoxycytidine, 5-carboxymethylester-uridine, 5-carboxymethylester-deoxyuridine, thieno- uridine, thieno-deoxyuridine, 5 -methoxy-cytidine, 5-methoxy-deoxycytidine, 5-methoxy-uridine, 5-methoxy-deoxyuridine, 5 -hydroxy-uridine, 5-hydroxy-deoxyuridine, 5-carboxy- uridine, 5-carboxy-deoxyuridine, 5-formyl-uridine, 5-formyl-deoxyuridine, 5-hydroxy-cytidine, 5-hydroxy-deoxycytidine, thieno-guanosine, thieno-deoxyguanosine, 5-hme-cytidine, 5-hme- deoxycytidine, 5-hme-uridine, 5-hme-deoxyuridine, 5-formyl-cytidine, 5-formyl-deoxycytidine, 5 -carboxy-cytidine, 5’-carboxy-deoxycytidine, N6-methyl-amino-adenosine, N6-methyl-amino- deoxyadenosine, 5,6-dihydro-5-methyluridine, 5,6-dihydro-5-methyl-deoxyuridine, Nl- methylpseudo-uridine, Nl-methylpseudo-deoxyuridine, N4-methyl-cytidine, N4-methyl- deoxycytidine, pseudoisocytidine, pseudoisodeoxycytidine, 2-aminopurine-ribose, 2- aminopurine-deoxyribose, 8-oxo-guanosine, 8-oxo-deoxyguanosine, aminoallyl-cytidine, aminoallyl-deoxycytidine, 2’-amino-deoxyguanosine, 2’ -amino-guanosine, 2’-azido- deoxyguanosine, 2’-azido-guanosine, 7-deaza-adenosine, 7-deaza-deoxyadenosine, 3’-O- methyl-uridine, 3’-O-methyl-deoxyuridine, 3’-O-methyl-cytidine, 3’-O-methyl-deoxycytidine, 3’-O-methyl-guanosine, 3’-O-methyl-deoxyguanosine, 3’-O-methyl-adenosine, 3’-O-methyl- deoxyadenosine, 3’-O-methyl-adenosine, 3’-O-methyl-deoxyadenosine, 2’-fluoro- deoxythymidine, 2’-fluoro-thymidine, 5-bromo-uridine, 5-bromo-deoxyuridine, 5-bromo- cytidine, 5-bromo-deoxycytidine, 8-azido-adenosine, 8-azido-deoxyadenosine, ara-adenosine, 2’-amino-deoxyadenosine, 2’ -amino-adenosine, 2’-azido-deoxyadenosine, 2’-azido-adenosine, 7-deaza- guanosine, 7-deaza-deoxy guanosine, 2’-O-Methyl-5-methyl-uridine, Nl-methyl- adenosine, Nl-methyl-deoxyadenosine, 2’-O-methyl-pseudouridine, 2’-O-methyl-2-amino- adenosine, N1 -methylguanosine, Nl-methyl-deoxyguanosine, 6- Aza-uridine, 6- Azadeoxyuridine, 6- Aza-cytidine, 6-aza-deoxycytidine, 2-thio-cytidine, 2-thio-deoxycytidine, 5,6- dihydro-uridine, 5,6-dihydro-deoxyuridine, ara-uridine, ara-cytidine, 2-thio-uridine, 2-thio- deoxyuridine, O6-methyl-guanosine, O6-methyl-deoxyguanosine, 2’-azido-deoxyuridine, 2’- azido-deoxycytidine, 2’-amino-deoxyuridine, 2’-amino-deoxycytidine, 4-thio-uridine, 5-methyl- uridine, xanthosine, puromycin, 2’-O-meythyl-inosine, inosine, 2’-O-methyl-uridine, 2’ 0- methyl-guanosine, 2’-O-methyl-cytidine, 2’-O-methyl-adenosine, N6-methyl-adenosine, 5-iodo- uridine, 5-iodo-cytidine, 2’-fluoro-deoxyuridine, 2 ’-fluoro-deoxy guanosine, 2’-fluoro- deoxycytidine, 2’-fluoro-deoxyadenosine, 6-chloro-purine-ribose, 8-aza-adenosine, 2-amino-6- chloro-purine -ribose, Cy3-deoxyuridine, 2-amino-adenosine, digoxigenin- 11 -dideoxyuridine, digoxigenin- 11 -uridine, digoxigenin- 11 -deoxyuridine, digoxigenin- 11 -dideoxyadenosine, digoxigenin- 11 -adenosine, digoxigenin- 11 -deoxy adenosine, digoxigenin- 11 -dideoxy guanosine, digoxigenin- 11 -guanosine, digoxigenin- 11 -deoxyguanosine, digoxigenin- 1 1 -dideoxycytidine, digoxigenin- 11 -cytidine, digoxigenin- 11 -deoxycytidine, aminoallyl-uridine, and aminoallyldeoxyuridine, including ddh versions thereof.

4. The compound of claim 1, wherein R2 comprises a hydrolyzable linker selected from: POM, SATE, DTE, cycloSal, HepDirect, ProTide, HDP, aminoacid phosphoramidite, and methylaryl haloalkylamidite.

5. The compound of claim 1, wherein R2 comprises a nonhydrolyzable linker is a methylene bridge or modification selected from: boranophosphate, thiophosphate, methylphosphonate, methylenediphosphonate, boranodiphosphate, thiomethylenediphosphate, methylthiophosphate, methylenecarbonyl, phosphorothioate, phosphoramidate, sulfamate, phosphoroamidate, sulfonate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoramidate triester and phosphorofluoridate6. The compound of claim 1, wherein X is O:

7. The compound of claim 1, wherein R1 is cytosine:

8. The compound of claim 1 , wherein R2 is diphosphate:

9. The compound of claim 1, wherein R3 is hydrogen:

11. The compound of claim 1, comprising a combination of embodiments selected from: X is O, R1 is cytosine, R2 is diphosphate, R3 is hydrogen and R4 is hydrogen.

12. The compound of claim 1, wherein X is O, and R1 is cytosine.

13. The compound of claim 1, wherein X is O and R2 is diphosphate.

14. The compound of claim 1, wherein X is O and R3 is hydrogen.

15. The compound of claim 1, wherein X is O and R4 is hydrogen.

6. The compound of claim 1 , wherein R 1 is cytosine, and R2 is diphosphate.

17. The compound of claim 1, wherein R1 is cytosine, and R3 is hydrogen.

18. The compound of claim 1, wherein R1 is cytosine, and R4 is hydrogen.

19. The compound of claim 1, wherein R2 is diphosphate, R3 is hydrogen.

20. The compound of claim 1 , wherein R2 is diphosphate, R4 is hydrogen.

21. The compound of claim 1, wherein R3 is hydrogen, R4 is hydrogen.

22. The compound of claim 1, wherein X is O, R1 is cytosine, R2 is diphosphate.

23. The compound of claim 1, wherein X is O, R1 is cytosine, R2 is diphosphate, R3 is hydrogen and R4 is hydrogen:

24. The compound of any of claim 1-23, wherein the choline moiety is conjugated to a biomolecule as a universal oral drug delivery strategy.

25. The compound of any of claim 1-23, wherein the choline moiety is conjugated to a biomolecule as a universal oral drug delivery strategy, wherein choline-conjugated pharmacophores / cargo can be delivered through the gut via promiscuous choline transporters.

26. A nutraceutical or pharmaceutical composition comprising a compound of any of claim 1- 23, and a pharmaceutically-acceptable excipient.

27. A nutraceutical or pharmaceutical composition comprising a compound of any of claim 1- 23, and a pharmaceutically-acceptable excipient, in pharmaceutically-acceptable unit dosage.

28. A method of providing a neutraceutical, pharmaceutical or therapeutic, comprising administering to a person in need thereof a composition of claim 26.

29. A method of delivering or improving delivery of poorly bioavailable small molecule drug across the gut, comprising delivering to the gut of a person in need thereof, a drug-choline conjugate according to the choline conjugation strategy described herein.

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