147127-19-3Relevant articles and documents
Tenofovirpurification method
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Paragraph 0047-0049; 0064, (2020/01/25)
The invention provides a tenofovir purification method, which comprises: S1) dissolving a tenofovir crude product in an alkali liquid, and adjusting the pH value of the system to 6-12; and S2) adjusting the pH value of the system to 2.8-3.4 with an acid, and separating the solid to obtain a pure tenofovir product. According to the invention, tenofovir is dissolved in an alkaline environment to carry out a hydrolysis reaction on the main impuritycondensation impurity, and the product can be precipitated in an acid environment, so that various impurities in the tenofovir can be effectively reduced, the product quality is improved, the yield and the purity are greatly improved, the operation is easy and convenient, and the method is easy to apply to industrial production.
Repurposing Antiviral Drugs for Orthogonal RNA-Catalyzed Labeling of RNA
Dey, Surjendu,Ghaem Maghami, Mohammad,H?bartner, Claudia,Lenz, Ann-Kathrin
, p. 9335 - 9339 (2020/04/17)
In vitro selected ribozymes are promising tools for site-specific labeling of RNA. Previously known nucleic acid catalysts attached fluorescently labeled adenosine or guanosine derivatives through 2′,5′-branched phosphodiester bonds to the RNA of interest. Herein, we report new ribozymes that use orthogonal substrates, derived from the antiviral drug tenofovir, and attach bioorthogonal functional groups, as well as affinity handles and fluorescent reporter units through a hydrolytically more stable phosphonate ester linkage. The tenofovir transferase ribozymes were identified by in vitro selection and are orthogonal to nucleotide transferase ribozymes. As genetically encodable functional RNAs, these ribozymes may be developed for potential cellular applications. The orthogonal ribozymes addressed desired target sites in large RNAs in vitro, as shown by fluorescent labeling of E. coli 16S and 23S rRNAs in total cellular RNA.
Inhibition of human purine nucleoside phosphorylase by tenofovir phosphate congeners
Votruba, Ivan,Tryznova, Jana,Brehova, Petra,Tloustova, Eva,Horska, Kvetoslava,Fanfrlik, Jindrich,Prenosil, Ondrej,Holy, Antonin
experimental part, p. 1249 - 1257 (2011/09/30)
The structure-activity study on the phosphates of phosphonomethoxypropyl derivatives of purine bases interacting with human purine nucleoside phosphorylase has shown that the most efficient inhibitors of the enzyme are (R)- and (S)-PMPGp with Ki ~ 1.9 × 10-8 and/or 2.2 × 10-8 mol/l. The kinetic experiments have proven, with the exception of both enantiomers of PMP-8-BrDAPp, strictly competitive character of inhibition for all ANP monophosphates tested. Bromine derivatives exhibited uncompetitive and mixed type of inhibition as well. These results were confirmed by docking studies. The substitution of purine moiety with the bromine at the position 8 lead to an allosteric binding of these compounds toward the enzyme.
SYNTHESIS OF ENANTIOMERIC N-(2-PHOSPHONOMETHOXYPROPYL) DERIVATIVES OF PURINE AND PYRIMIDINE BASES. I. THE STEPWISE APPROACH
Holy, Antonin,Masojidkova, Milena
, p. 1196 - 1212 (2007/10/02)
The (R)- and (S)-N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases (PMP derivatives) exhibit very high activity against retroviruses.This paper describes the synthesis of enantiomeric 9-(2-phosphonomethoxypropyl)adenines (I and XXVII), 9-(2-phosphonomethoxypropyl)-2,6-diaminopurines (II and XXXI), 9-(2-phosphonomethoxypropyl)guanines (III and XXIX) and 1-(R)-(2-phosphonomethoxypropyl)cytosine (XIX) by alkylation of N-protected N-(2-hydroxypropyl) derivatives of the corresponding bases with bis(2-propyl) p-toluenesulfonyloxymethylphosphonate (X), followed by stepwise N- and O-deprotection of the intermediates.The key intermediates, N-(2-hydropxypropyl) derivatives IX and XXV, were obtained by alkylation of the appropriate heterocyclic base with (R)- or (S)-2-(2-tetrahydropyranyloxy)propyl p-toluenesulfonate (VII or XXIII) ans acid hydrolysis of the resulting N- derivatives VIII and XXII.The chiral synthons were prepared by tosylation of (R)- or (S)-2-(2-tetrahydropyranyloxy)propanol (VI or XXI) available by reduction of enantiomeric alkyl 2-O-tetrahydropyranyllactates V and XXI with sodium bis(2-methoxyethyoxy)aluminum hydride.This approach was used for the synthsis of cytosine, adenine and 2,6-diaminopurine derivatives, while compounds derived from guanine were prepared by hydrolysis of 2-amino-6-chloropurine intermediates.Cytosine derivative IXe was also synthesized by alkylation of 4-methoxy-2-pyrimidone followed by ammonolysis of the intermediate IXf.
SYNTHESIS OF ENANTIOMERIC N-(2-PHOSPHONOMETHOXYPROPYL)DERIVATIVES OF PURINE AND PYRIMIDINE BASES. II. THE SYNTHON APPROACH
Holy, Antonin,Dvorakova, Hana,Masojidkova, Milena
, p. 1390 - 1409 (2007/10/02)
Another approach to (R)- and (S)-N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases (PMP derivatives) I and II is described, consisting in alkylation of the heterocyclic base with (R)- and (S)-2-propyl p-toluenesulfonates (X and XVIII) followed by transsilylation of the intermediary N- derivatives XI and XIX.The key intermediates X and XVIII were obtained from 1-benzyloxypropanols VI and XIV by two routes: (i) condensation with bis(2-propyl) p-toluenesulfonyloxymethylphosphonate (XIII), hydrogenolysis of the obtained 1-benzyloxy-2-bis(2-propyl)phosphonylmethoxypropanes VIII and XVI over Pd/C to 2-bis(2-propyl)phosphonylmethoxypropanols IX and XVII and tosylation of the latter or (ii) chloromethylation of compounds VI and XIV and subsequent reaction of the chloromethyl ethers VII and XV with tris(2-propyl) phosphite and further processing of the benzyl ethers VIII and XVI analogous to the enantiomeric propanols IX and XVII.This approach was used for the synthesis of derivatives of adenine (Ia, IIa), 2,6-diaminopurine (Ib, IIb) and 3-deazaadenine (Ic, IIc).Their guanine counterparts Ie and IIe were prepared by hydrolysis of 2-amino-6-chloropurine intermediates XId and XIXd. 6-Chloropurine was converted into diester XIi by reaction with tosylate X, which on reaction with thiourea and subsequent ester cleavage afforded the 6-thiopurine derivative Ij.Analogously, 2-amino-6-chloropurine derivative XId reacted with thiourea to give 9-(R)-(2-phosphonomethoxypropyl)-2-thioguanine (If), or with dimethylamine under formation of (2-phosphonomethoxypropyl)-2-amino-6-dimethylaminopurine (Ig).Hydrogenolysis of compound XId gave 9-(R)-(2-phosphonomethoxypropyl)-2-aminopurine (Ik).Hydrolytic deamination of adenine derivatives Ia and IIa led to enantiomeric (2-phoshonomethoxypropyl)hypoxanthines Ih and IIh.
PHOSPHONYLMETHOXYALKYL AND PHOSPHONYLALKYL DERIVATIVES OF ADENINE
Rosenberg, Ivan,Holy, Antonin,Masojidkova, Milena
, p. 2753 - 2777 (2007/10/02)
Analogues of the antivirals (2S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (Ia) and 9-(2-phosphonylmethoxyethyl)adenine (Ib), modified in the alkyl chain, are described.The phosphonylmethoxyalkyl derivatives were prepared by condensation of sodium alkoxides of hydroxyalkyladenines (or their N-protected derivatives) with dimethyl p-toluenesulfonyloxymethanephosphonate (II) followed by alkaline hydrolysis and reactions with halotrimethylsilane, or by reaction of vicinal dihydroxyalkyl derivatives with chloromethanephosphonyl dichloride (XIV) and subsequent cyclization of the intermediates XV in aqueous alkali.In the second case the pure regioisomers were also obtained from substituted dihydroxy derivatives with one free hydroxyl group.The following compounds were prepared in this way: 3-O-methyl ether IIIc and 3-O-octyl ether IVc, 9-(3-phosphonylmethoxypropyl)- (Vc), 9-(4-phosphonylmethoxybutyl)- (Vf), 9-(5-phosphonylmethoxypentyl) (Vi), 9-(2-phosphonylmethoxypropyl)- (VIc), 9-(1-phosphonylmethoxy-3-hydroxy-2-propyl)- (XIIc), 9-(2-methoxy-3-phosphonylmethoxypropyl)- (XIIIc), erythro-9-(2-phosphonylmethoxy-3,4-dihydroxybutyl)- (VIIc), and threo-9-(4-phosphonylmethoxy-2,3-dihydroxybutyl)adenine (IXc) and its enantiomer (Xc). 9-(2-Phosphonylmethoxy-3,3-dihydroxypropyl)adenine (VIII) was obtained by oxidation of VIIc with sodium periodate, 9-(2-phosphonylmethoxyethoxymethyl)adenine (XIc) by reaction of II with sodium salt of 9-(2-hydroxyethoxymethyl)adenine (XIa). 9-(1,2-Dihydroxy-2-methyl-3-propyl)adenine 1- and 2-phosphonylmethyl ether (XVIb), 9-(3,4-dihydroxybutyl)adenine 3- and 4-phosphonylmethyl ether (XVIIb) and 9-(2,3-dihydroxybutyl)adenine 2- and 3-phosphonylmethyl ether (XVIIIb) were prepared by reaction chloromethanephosphonyl dichloride (XIV) followed by alkaline treatment.Analogous reaction was also employed in the preparation of regioisomerically pure 1-phosphonylmethyl ethers of 9-(1,2-dihydroxy-3-butyl)adenine (XXIV), 9-(1,2-dihydroxy-2-methyl-3-propyl)adenine (XVIb) and 9-(1,2-dihydroxy-3-nonyl)adenine (XXV).Alkylation of adenine with diethyl chloromethoxymethanephosphonate (XXVII) followed by hydrolysis afforded 9-(phosphonylmethoxymethyl)adenine (XXVIIIb). 9-(Phosphonylmethyl)adenine (XLI) was obtained by condensation of adenine with compound II.Conversion of 9-(ω-hydroxyalkyl)adenines into the ω-halogenoalkyl derivatives followed by reaction with trialkyl phosphite and cleavage was used in the preparation of 9-(2-phosphonylethyl)adenine (XXXIVa), 9-(4-phosphonylbutyl)adenine (XXXIVb) and 9-(2-phosphonylethoxymethyl)adenine (XXXIX). 9-(2-Phosphonyl-2-hydroxyethyl)adenine (Lc) and 9-(3-phosphonyl-3-hydroxypropyl)adenine (Lb) were synthesized by treatment of ω-(adenin-9-yl)alkanals with dialkyl phosphite and subsequent cleavage with halogenotrimethylsilane; the same procedure converted 9-(2-oxopropyl)adenine (XLVIIIa) into 9-(2-phosphonyl-2-hydroxypropyl)adenine (La).
