- Dihydronicotinamide riboside is a potent NAD concentration enhancer in vitro and in vivo
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Interest in pharmacological agents capable of increasing cellular NAD concentrations has stimulated investigations of nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). NR and NMN require large dosages for effect. Herein, we describe synthesis of dihydronicotinamide riboside (NRH) and the discovery that NRH is a potent NAD concentration-enhancing agent, which acts within as little as 1 h after administration to mammalian cells to increase NAD concentrations by 2.5–10-fold over control values. Comparisons with NR and NMN show that in every instance, NRH provides greater NAD increases at equivalent concentrations. NRH also provides substantial NAD increases in tissues when administered by intraperitoneal injection to C57BL/6J mice. NRH substantially increases NAD/NADH ratio in cultured cells and in liver and no induction of apoptotic markers or significant increases in lactate levels in cells. Cells treated with NRH are resistant to cell death caused by NAD-depleting genotoxins such as hydrogen peroxide and methylmethane sulfonate. Studies to identify its biochemical mechanism of action showed that it does not inhibit NAD consumption, suggesting that it acts as a biochemical precursor to NAD. Cell lysates possess an ATP-dependent kinase activity that efficiently converts NRH to the compound NMNH, but independent of Nrk1 or Nrk2. These studies identify a putative new metabolic pathway to NAD and a potent pharmacologic agent for NAD concentration enhancement in cells and tissues.
- Yang, Yue,Mohammed, Farheen Sultana,Zhang, Ning,Sauve, Anthony A.
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- Preparation method and use of hydrogenated nicotinamide ribose
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The invention discloses a preparation method of hydrogenated nicotinamide ribose. The preparation method comprises the following steps: reacting chlorate of nicotinamide ribose with trifluoromethanesulfonate in a solvent, and separating out trifluoromethanesulfonate of nicotinamide ribose by using a concentration crystallization method; putting the trifluoromethanesulfonate of nicotinamide ribose and a reducing agent into a micro-channel reactor in inert and weakly alkaline atmospheres, and reacting at a low temperature to obtain a crude product; and purifying the crude product by using a high performance liquid chromatography to obtain the purified hydrogenated nicotinamide ribose. The hydrogenated nicotinamide ribose is synthesized by taking the trifluoromethanesulfonate of the low-cost compound nicotinamide ribose as a raw material through a low-temperature chemical catalysis method, the cost is low, the purity is high, the hydrogenated nicotinamide ribose is prepared from the trifluoromethanesulfonate of the nicotinamide ribose through a one-step method, and preparation time of the hydrogenated nicotinamide ribose is greatly shortened.
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Paragraph 0040-0089
(2022/01/20)
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- Dihydronicotinamide riboside: synthesis from nicotinamide riboside chloride, purification and stability studies
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In the present work, we describe an efficient method for scalable synthesis and purification of 1,4-dihydronicotinamide riboside (NRH) from commercially available nicotinamide riboside chloride (NRCl) and in the presence of sodium dithionate as a reducing agent. NRH is industrially relevant as the most effective, synthetic NAD+precursor. We demonstrated that solid phase synthesis cannot be used for the reduction of NRCl to NRH in high yield, whereas a reduction reaction in water at room temperature under anaerobic conditions is shown to be very effective, reaching a 55% isolation yield. For the first time, by using common column chromatography, we were able to highly purify this sensitive bio-compound with good yield. A series of identifications and analyses including HPLC, NMR, LC-MS, FTIR, and UV-vis spectroscopy were performed on the purified sample, confirming the structure of NRH as well as its purity to be 96%. Thermal analysis of NRH showed higher thermal stability compared to NRCl, and with two major weight losses, one at 218 °C and another at 805 °C. We also investigated the long term stability effects of temperature, pH, light, and oxygen (as air) on the NRH in aqueous solutions. Our results show that NRH can be oxidized in the presence of oxygen, and it hydrolyzed quickly in acidic conditions. It was also found that the degradation rate is lower under a N2atmosphere, at lower temperatures, and under basic pH conditions.
- Abbaspourrad, Alireza,Enayati, Mojtaba,Khazdooz, Leila,Madarshahian, Sara,Ufheil, Gerhard,Wooster, Timothy J.,Zarei, Amin
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p. 21036 - 21047
(2021/07/01)
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- Chemical and Biochemical Reactivity of the Reduced Forms of Nicotinamide Riboside
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All life forms require nicotinamide adenine dinucleotide, NAD+, and its reduced form NADH. They are redox partners in hundreds of cellular enzymatic reactions. Changes in the intracellular levels of total NAD (NAD+ + NADH) and the (NAD+/NADH) ratio can cause cellular dysfunction. When not present in protein complexes, NADH and its phosphorylated form NADPH degrade through intricate mechanisms. Replenishment of a declining total NAD pool can be achieved with biosynthetic precursors that include one of the reduced forms of nicotinamide riboside (NR+), NRH. NRH, like NADH and NADPH, is prone to degradation via oxidation, hydration, and isomerization and, as such, is an excellent model compound to rationalize the nonenzymatic metabolism of NAD(P)H in a biological context. Here, we report on the stability of NRH and its propensity to isomerize and irreversibly degrade. We also report the preparation of two of its naturally occurring isomers, their chemical stability, their reactivity toward NRH-processing enzymes, and their cell-specific cytotoxicity. Furthermore, we identify a mechanism by which NRH degradation causes covalent peptide modifications, a process that could expose a novel type of NADH-protein modifications and correlate NADH accumulation with protein aging. This work highlights the current limitations in detecting NADH's endogenous catabolites and in establishing the capacity for inducing cellular dysfunction.
- Makarov, Mikhail V.,Hayat, Faisal,Graves, Briley,Sonavane, Manoj,Salter, Edward A.,Wierzbicki, Andrzej,Gassman, Natalie R.,Migaud, Marie E.
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p. 604 - 614
(2021/05/04)
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- Preparation method of nicotinamide ribose, reduction state and salt of nicotinamide ribose
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The invention belongs to the technical field of organic synthesis. The invention discloses a preparation method of nicotinamide ribose. The method comprises the following steps: reacting an intermediate A with nicotinamide in the presence of TMSOTf to obt
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- REDUCED NICOTINAMIDERIBOSIDES FOR TREATING OR PREVENTING KIDNEY DISEASE
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The present invention provides compounds and compositions containing reduced nicotinamide riboside for use in methods of prevention and/or treatment of kidney diseases and conditions. In one embodiment of the invention, said compounds and compositions of the invention improve kidney function by reducing formation of kidney cysts, reducing glomerule dilatation, reducing renal cell apoptosis and preventing increases in blood urea nitrogen. In another embodiment of the invention, compounds and compositions of the invention may be used in methods to prevent and/or treat acute kidney injury (AKI), chronic kidney disease, diabetic nephropathy, focal segmental glomerulosclerosis, nephrotic syndrome, renal fibrosis and kidney cancer.
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Page/Page column 15
(2020/12/29)
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- Scalable syntheses of traceable ribosylated NAD+ precursors
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Nicotinamide adenine dinucleotide, NAD+, is an essential cofactor and substrate for many cellular enzymes. Its sustained intracellular levels have been linked to improved physiological end points in a range of metabolic diseases. Biosynthetic precursors to NAD+ include nicotinic acid, nicotinamide, the ribosylated parents and the phosphorylated form of the ribosylated parents. By combining solvent-assisted mechanochemistry and sealed reaction conditions, access to the ribosylated NAD+ precursors and to the isotopologues of NAD+ precursors was achieved in high yields and levels of purity. The latter is critical as it offers means to better trace biosynthetic pathways to NAD+, investigate the multifaceted roles of the intracellular NAD+ pools, and better exploit NAD+ biology.
- Makarov,Harris,Rodrigues,Migaud
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supporting information
p. 8716 - 8720
(2019/10/16)
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- EFFICIENT AND SCALABLE SYNTHESES OF NICOTINOYL RIBOSIDES AND REDUCED NICOTINOYL RIBOSIDES, MODIFIED DERIVATIVES THEREOF, PHOSPHORYLATED ANALOGS THEREOF, ADENYLYL DINUCLEOTIDE CONJUGATES THEREOF, AND NOVEL CRYSTALLINE FORMS THEREOF
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The present disclosure provides methods of making nicotinoyl riboside compounds or derivatives of formula (I): wherein X?, Z1, Z2, n, R1, R2, R3, R4, R5, R6, R7, and R8 are described herein, reduced analogs thereof, modified derivatives thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof, or salts, solvates, or prodrugs thereof; and novel crystalline forms thereof.
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- NICOTINAMIDE RIBOSIDE AND NICOTINAMIDE MONONUCLEOTIDE DERIVATIVES FOR USE IN THE TREATMENTS OF MITOCHONDRIAL-RELATED DISEASES
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Provided herein are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, and compositions comprising such compounds that are useful for increasing the amount of NAD+ in cells. Also disclosed are methods of using the disclosed compounds and compositions for treating mitochondrial-related diseases or disorders.
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- SYNTHESES, ACTIVITIES, AND METHODS OF USE OF DIHYDRONICOTINAMIDE RIBOSIDE DERIVATIVES
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Disclosed is a compound of formula (I): wherein R1, R2, R3, and are as defined herein. Also disclosed are methods for increasing mammalian cell NAD+ production and improving mitochondrial cell densities comprising administering to a cell the compound or a salt thereof.
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Paragraph 0091; 0092
(2017/02/09)
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- METHODS OF PREPARING NICOTINAMIDE RIBOSIDE AND DERIVATIVES THEREOF
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The invention relates to methods of preparing nicotinamide riboside and derivatives thereof. In an aspect, the invention relates to a method of preparing a compound of formula (I), wherein n is 0 or 1; m is 0 or 1; Y is O or S; R1 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted primary or secondary amino, and substituted or unsubstituted azido; R2- R5, which may be the same or different, are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl; and X- is an anion, selected from an anion of a substituted or unsubstituted carboxylic acid, a halide, a substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or unsubstituted sulfate, a substituted or unsubstituted carbonate, and a substituted or unsubstituted carbamate.
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Page/Page column 20
(2015/02/25)
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