NAD+ analogue, as well as synthesis and use thereof

A technology of analogs and synthetic methods, applied in sugar derivatives, adding compounds to stimulate growth, organic chemistry, etc., can solve the problems of simple structure of cofactors, many by-products, difficult separation, etc., and achieve simple and easy separation and purification , mild reaction conditions, and easy-to-obtain raw materials

Active Publication Date: 2009-08-05
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The above work is based on the NAD + Based on the chemical modification of the original structure, it is difficult to overcome the shortcomings of its chemical instability, chemical synthesis and separation difficulties, etc.
[0009] H.C.Lo et al. (Inorg.Chem.2001, 40, 6705-6716.) used methanol as a substitute for adenosine monophosphate (AMP) and nicotinamide mononucleotide under DCC / DMAP to synthesize NAD + analog However, this method has low yield, many by-products, difficult separation, and the product is easily decomposed during the separation process.
In addition, if other alcohols are used as a substitute for the adenosine monophosphate (AMP) part, no suitable solvent can be found to dissolve nicotinamide mononucleotide, and the 2' and 3' hydroxyl groups on the sugar ring will also participate in the reaction. So this method is not suitable for the synthesis of NAD of the present invention + analog
[0010] H.C.Lo et al. (Angew.Chem.Int.Ed.2002, 41, 478-481.) reported an example of using the above analogs as cofactors of horse liver dehydrogenase (HLADH) to reduce ketones to chiral alcohols, However, the reducing agent used is the rare metal Rh, which is expensive, cumbersome to operate, sensitive to air, and the structure of the cofactor is too simple, and the combination with the enzyme is not tight enough.

Method used

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  • NAD+ analogue, as well as synthesis and use thereof
  • NAD+ analogue, as well as synthesis and use thereof
  • NAD+ analogue, as well as synthesis and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 0.63mmol Ac 2 NMN Dissolve in 7ml pyridine and 7ml DMF mixed solvent, add 2-phenylethanol (200μl, 1.67mmol), add 2,4,6-triisopropylbenzenesulfonyl chloride (TPS-Cl) (757mg, 2.5mmol), 10 The reaction was stirred at °C for 10 h, the solvent was removed under reduced pressure, 10 ml of water was added dropwise, washed with dichloromethane, the aqueous phase was concentrated, and the product was collected by reverse-phase silica gel column chromatography, and concentrated to obtain a yellow syrupy solid.

[0037] The above product was dissolved in 0.7ml methanol, cooled to -5°C, and 7M NH was added. 3 115 μl of methanol solution of 115 μl, the mixture was stirred at -5 °C overnight, TLC detected until the reaction was complete, the solvent was removed, 1 ml of water was added to the residue, and the product was collected by reverse-phase silica gel column chromatography, concentrated, and then passed through anion exchange resin (201× 4. HCO 2 - type), concentrated, ly...

Embodiment 2

[0051] With the method of embodiment 1; the difference with embodiment 1 is that the alcohol used is The reaction temperature was 30°C, the reaction time was 38h, the condensation reagent used was 1-p-nitrobenzenesulfonic acid-1,2,4-triazole, and the molar ratio of pyridinium salt, alcohol and condensation reagent was 1:1:5, Yield: 59%.

[0052]

[0053] 1 H NMR (400MHz, D 2 O): δ 0.75(t, 2H), 1.23(q, 2H), 1.44(t, 2H), 3.75(q, 2H), 4.03(d, J=5.32Hz, 1H), 4.20(d, J= 10.28Hz, 1H), 4.42(t, J=5.08Hz, 1H), 4.51(s, 1H), 6.11(d, J=5.12Hz, 1H), 9.01(d, J=6.04, 1H), 8.88( d, J=7.56Hz, 1H), 8.18 (t, J=7.44Hz, 1H), 9.34 (s, 1H).

[0054] 13 C NMR (100MHz, D 2 O): δ 168.2, 148.4, 144.9, 142.2, 136.4, 130.9, 102.3, 89.7, 80.2, 73.5, 68.7, 66.8, 34.4, 20.8, 15.4.

[0055] 31 P NMR (160MHz, D 2 O): δ 0.57.

[0056] HRMS: calcd for C 15 H 23 N 2 O 8 P(M+H + )391.1230, found(M+H + )391.1244.

[0057] The compound has a molecular weight of 390.12, has UV absorption at 266 n...

Embodiment 3

[0065] With the method of embodiment 1; the difference with embodiment 1 is that the alcohol used is The reaction temperature is 35°C, the reaction time is 38h, the molar ratio of pyridinium salt, alcohol and condensation reagent is 1:3:8, the volume ratio of DMF:Py=1:8, the yield: 12%.

[0066]

[0067] 1 H NMR (400MHz, D 2 O): δ 1.20(t, 2H), 1.28(d, 6H), 1.42(d, 3H), 1.51(d, 3H), 1.69(s, 3H), 3.74(q, 2H), 4.01(dd, J=4.92, 10.4Hz, 1H), 4.17(dd, J=3.96, 9.92Hz, 1H), 4.28(s, 1H), 4.43(s, 1H), 4.48(s, 1H), 6.09(d, J = 5.04, 1H), 8.16 (t, J=7.04, 1H), 8.87 (d, J=8.04, 1H), 9.14 (d, J=6.2, 1H), 9.32 (s, 1H).

[0068] 13 C NMR (100MHz, D 2 O): δ 167.5, 148.4, 144.7, 141.9, 141.2, 136.2, 131.6, 131.0, 130.8, 128.9, 65.3, 45.7, 42.6, 38.2, 31.6, 29.3, 19.8.

[0069] 31 P NMR (160MHz, D 2 O): δ 0.63.

[0070] HRMS: calcd for C 23 H 33 N 2 O 8 P(M+H + )497.2210, found(M+H + )497.2254.

[0071] The compound has a molecular weight of 496.22, has UV absorption at 266 n...

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Abstract

The invention discloses an NAD analogue as well as the synthesis and the application thereof. The structural formula I of the NAD analogue is a di-phosphate ester compound generated by reacting nicotinamide mononucleotide and corresponding alcohol. An R is a C4-C15 saturated or unsaturated alkyl or saturated or unsaturated alkyl A containing C2-C10 of a heteroatom; and (the R details as the formula II). The NAD analogue can promote the growth of the microorganisms such as colibacillus, saccharomyces cerevisiae, and the like; and the NAD analogue can be also taken as the dehydrogenase cofactor used for catalytic oxidation and reduction reaction.

Description

technical field [0001] The present invention relates to a class of NAD + Analogs, specifically saturated and unsaturated alkanes with various substituents, phosphodiester compounds whose aromatic hydrocarbons are adenosine monophosphate (AMP) analogs, and the synthesis of NAD with a series of condensation reagents + Analogs - NAD with phosphodiester structure + methods of analogs, and the compounds act as growth promoters for microorganisms such as Escherichia coli and Saccharomyces cerevisiae; and also serve as cofactors for dehydrogenases in catalyzing redox reactions. Background technique [0002] Nicotinamide adenine dinucleotide (NAD) + ) and its corresponding reduced state (NADH), commonly known as coenzyme I, is an indispensable small molecule compound for living organisms and participates in redox metabolism and a series of other important biochemical processes in living organisms. Its structural formula is as follows: [0003] [0004] Adenosine monophosphate ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/048C12N1/38
Inventor 赵宗保刘武军吴思国侯淑华
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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