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CN-121974969-A - Synthesis method of ADPr-phenolic compound with adjustable alpha/beta-selectivity, compound library and application of compound library

CN121974969ACN 121974969 ACN121974969 ACN 121974969ACN-121974969-A

Abstract

The invention discloses a synthesis method, a compound library and application of an alpha/beta-selectivity adjustable ADPr-phenolic compound, wherein beta-nicotinamide adenine dinucleotide and the phenolic compound are subjected to one-step nucleophilic substitution reaction to generate ADPr-phenolic compound in the presence of ionic liquid, the ADPr-phenolic compound can be efficiently synthesized by precisely regulating and controlling an ionic liquid system, a reaction substrate proportion, a reaction temperature or/and a reaction time, the alpha/beta-stereoselectivity of a product is effectively controlled, the product with the high beta-selectivity of more than 99% or the product with the high alpha-selectivity of up to 88% is obtained, and the synthesized ADPr-phenolic compound can be used for preparing an ADP-ribose hydrolase ARH3 inhibitor, and can be used for preparing and adjusting NAD+ metabolism, researching protein ADP-ribosylation modification, serving as a metabolic tracer agent and serving as an inhibitor or tool molecule aiming at other targets.

Inventors

  • ZHU ANLIAN
  • LI LINGJUN
  • LI MUNONG
  • Fan Dongshuang
  • YOU YANBO

Assignees

  • 河南师范大学

Dates

Publication Date
20260505
Application Date
20251224

Claims (10)

  1. 1. A synthesis method of a ADPr-phenolic compound with adjustable alpha/beta-selectivity is characterized in that the specific synthesis process comprises the steps of carrying out one-step nucleophilic substitution reaction on beta-nicotinamide adenine dinucleotide and the phenolic compound in the presence of ionic liquid to generate ADPr-phenolic compound; the phenolic compound is phenol, substituted phenol, naphthol, coumarin, ferulic acid ester or Boc-tyrosine methyl ester, wherein the substituent on the substituted phenol is selected from alkyl, alkoxy, halogen or nitro; the ionic liquid is selected from one of the following systems: An ionic liquid consisting of an organic base cation and a halogen anion, BF 4 - 、PF 6 - 、CF 3 COO - 、NTf 2 - or CF 3 SO 3 - ; An ionic liquid composed of organic base cations and phenoxy anions; An ionic liquid system consisting of an organic base cation, a phenoxy anion and an excess of free phenol; Through accurately regulating and controlling an ionic liquid system, a reaction substrate proportion, a reaction temperature or/and a reaction time, ADPr-phenolic compounds can be efficiently synthesized, and the high-efficiency control of the alpha/beta-stereoselectivity of the product is realized, so that the product with the high beta-selectivity of more than 99% or with the high alpha-selectivity of up to 88% is obtained.
  2. 2. The method for synthesizing the α/β -selective and adjustable ADPr-phenol compound according to claim 1, wherein the reaction temperature in the synthesis process is 70-80 ℃.
  3. 3. The method for synthesizing α/β -selective tunable ADPr-phenol compound of claim 1, wherein the substituent on the substituted phenol is C 1-6 alkyl or C 1-6 alkoxy.
  4. 4. The method for synthesizing α/β -selective tunable ADPr-phenolic compounds according to claim 1, wherein the ionic liquid system is one or more of [DABCO][Cl]、[DBU][Cl]、[DMA16][Cl]、[TMG][Cl]、[DABCO][Br]、[DBU][Br]、[DMA16][Br]、[TMG][Br]、[DMEA][Br]、[DABCO][I]、[DBU][I]、[TMG][I]、[DMA16][I]、[N-Methylpiperidine][I]、[DABCO][BF 4 ]、[DBU][BF 4 ]、[DMA16][BF 4 ]、[TMG][BF 4 ]、[N-Methylpiperidine][BF 4 ]、[DMEA][BF 4 ]、[DIPEA][BF 4 ]、[TEA][BF 4 ]、[TEOA][BF 4 ]、[MIM][BF 4 ]、[L(+)-Arginine][BF 4 ]、[DABCO][PF 6 ]、[DABCO][CF 3 COO]、[DBU][CF 3 COO]、[DABCO][NTf 2 ]、[TMG][NTf 2 ]、[DBU][NTf 2 ]、[N-Methylpiperidine][NTf 2 ]、[L(+)-Arginine][NTf 2 ]、[N-Methylpiperidine][CF 3 SO 3 ] or [ DABCO ] [ CF 3 SO 3 ], or the ionic liquid system is [TMG][ArO - ]、[DBU][ArO - ]、[DABCO][ArO - ]、[TMG][p-NO 2 -PhO-]、[DBU][p-NO 2 -PhO-] or [ DABCO ] [ p-NO 2 -PhO- ], or the ionic liquid system is [ TMG ] [ ArO - ]-ArOH、[DBU][ArO - ] -ArOH or [ DABCO ] [ ArO - ] -ArOH.
  5. 5. Use of ADPr-phenolic compounds prepared by a method according to any one of claims 1 to 4 in the preparation of ADP-ribose hydrolase inhibitors.
  6. 6. The method according to claim 5, wherein the ADP-ribose hydrolase is ADP-ribosyl hydrolase 3.
  7. 7. A pharmaceutical composition comprising a therapeutically effective amount of ADPr-phenolic compound prepared by the process of any one of claims 1 to 4 and a pharmaceutically acceptable salt or carrier.
  8. 8. Use of ADPr-phenolic compounds prepared according to the method of any one of claims 1-4 in the preparation of a product for modulating NAD + metabolism, detecting ADP-ribosylase activity or as a metabolic tracer.
  9. 9. Use of ADPr-phenolic compounds prepared according to the method of any one of claims 1 to 4 in the preparation of a medicament or tool molecule for inhibiting the activity of poly (ADP-ribose) polymerase (PARP) or viral macrodomain.
  10. The ADPr-phenolic compound library is characterized in that the ADPr-phenolic compound specifically comprises alpha-ADPr-p-Cl-phenol, alpha-ADPr-m-MeO-phenol, alpha-ADPr-p-Me-phenol, alpha-ADPr-p-I-phenol, alpha-ADPr-pNP, alpha-ADPr-coumarin, alpha-ADPr-tyrosine methyl ester (Boc protection), alpha-ADPr-phenol, alpha-ADPr-o-MeO-phenol, alpha-ADPr-p-Br-phenol, alpha-ADPr-1-naphthol, alpha-ADPr-2-naphthol, alpha-ADPr-ferulic acid methyl ester, beta-ADPr-p-Cl-phenol, beta-ADPr-m-MeO-phenol, beta-ADPr-p-Me-phenol, beta-2-p-I-phenol, beta-ADPr-pNP, beta-2-naphthol, beta-methyl ester, beta-ADPr-p-naphthol, beta-ADPr-methyl ester, beta-ADPr-p-Cl-phenol, beta-ADPr-methyl ester, beta-ADPr-p-methyl ester, beta-ADPr-p-methyl ester; ADPr-phenolic compounds have the structural formula:

Description

Synthesis method of ADPr-phenolic compound with adjustable alpha/beta-selectivity, compound library and application of compound library Technical Field The invention belongs to the technical field of ADPr-phenolic compound synthesis and application, and particularly relates to a synthesis method of a ADPr-phenolic compound with adjustable alpha/beta-selectivity, a compound library and application thereof. Background ADPr-phenolic compounds are key structural units in protein tyrosine ADP-ribosylation modification, and are also an important NAD + metabolic tracer and candidate drugs with broad-spectrum antiviral potential. However, their chemical synthesis has long faced significant challenges. Conventional multistep syntheses (Drown,B.S.,Shirai,T.,Rack,J.G.M.,Ahel,I.&Hergenrother,P.J.MonitoringPoly(ADPribosyl)glycohydrolaseActivitywithaContinuous FluorescentSubstrate.CellChem.Biol.25,1562-1570(2018)) typically require 8-11 reactions, involve lengthy protection and deprotection steps, harsh reaction conditions, and inefficient phosphorylation/pyrophosphorylation couplings, with relatively low overall yields. Particularly, α -isomers having important biological functions are difficult to obtain efficiently and selectively by conventional chemical methods. In the prior art, although attempts to directly introduce a phenol oxygen group by thermal dissolution of NAD + have been reported, problems such as low yield, poor selectivity (usually only the beta isomer can be obtained) and the like are common, and controllable synthesis of the alpha isomer cannot be realized. Therefore, the development of the synthesis method has simple steps, mild conditions, can accurately regulate and control the alpha/beta-stereoselectivity as required, is applicable to the synthesis method of various phenol substrates, and has important significance for promoting the functional research, tool development and drug creation of the molecules. Disclosure of Invention One of the purposes of the invention is to overcome the defects of the prior art and provide a method for synthesizing ADPr-phenolic compounds with adjustable alpha/beta selectivity, which has the advantages of simple operation, mild condition and wide substrate application range. The second object of the present invention is to provide the use of ADPr-phenolic compounds synthesized by the above-described method for the preparation of ADP-ribose hydrolase ARH3 inhibitors. It is a further object of the present invention to provide the broad use of ADPr-phenolic compounds synthesized by the above method for the preparation of molecules useful for modulating NAD + metabolism, for studying protein ADP-ribosylation modifications, as metabolic tracers and as inhibitors or tools against other targets (e.g. PARP, viral macrodomains, etc.). It is a fourth object of the present invention to provide specific ADPr-phenolic compounds of defined structure and biological activity synthesized by the above-described method. The invention adopts the following technical scheme that the synthesis method of ADPr-phenolic compound with adjustable alpha/beta-selectivity comprises the specific synthesis process that beta-nicotinamide adenine dinucleotide (beta-NAD +) and phenolic compound are subjected to one-step nucleophilic substitution reaction in the presence of ionic liquid to generate ADPr-phenolic compound; the phenolic compound is phenol, substituted phenol, naphthol, coumarin, ferulic acid ester or Boc-tyrosine methyl ester, wherein the substituent on the substituted phenol is selected from alkyl, alkoxy, halogen or nitro; the ionic liquid is selected from one of the following systems: An ionic liquid consisting of an organic base cation and a halogen anion, BF 4-、PF6-、CF3COO-、NTf2- or CF 3SO3-; An ionic liquid composed of organic base cations and phenoxy anions; An ionic liquid system consisting of an organic base cation, a phenoxy anion and an excess of free phenol; The organic base cation is selected from cations of 1, 3-Tetramethylguanidine (TMG), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 4-diazabicyclo [2.2.2] octane (DABCO), N-dimethylhexadecylamine (DMA 16), N-Dimethylethylamine (DMEA), N-methylpiperidine (N-METHYLPIPERIDINE), N-Diisopropylethylamine (DIPEA), triethylamine (TEA), triethanolamine (TEOA), N-methylimidazole (MIM) or L-Arginine (L (+) -Arginine); Through accurately regulating and controlling an ionic liquid system, a reaction substrate proportion, a reaction temperature or/and a reaction time, ADPr-phenolic compounds can be efficiently synthesized, and the high-efficiency control of the alpha/beta-stereoselectivity of the product is realized, so that the product with the high beta-selectivity of more than 99% or with the high alpha-selectivity of up to 88% is obtained. Further, the reaction temperature in the synthesis process is 70-80 ℃. Further, the substituent on the substituted phenol is a C 1-6 alkyl group or a C 1-6 alkoxy group. Further, the ionic liquid