An Improved Synthesis of N6-(6-Aminohexyl)FAD

Abstract

We report an improved synthesis of N ⁶-(6-aminohexyl)FAD (1) using an efficient one-pot conversion of inosine to the N-trifluoroacetyl protected N ⁶-(6-aminohexyl)adenosine 3. The 5′-O-phosphorylated AMP derivative 4, activated as the imidazolide, was coupled with commercial sodium riboflavin phosphate by using 18-crown-6 in DMF.     

Synthesis and bioactivity of 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-xylopyranosyl-1,3,4-oxa(thia)diazol-2-amines

A series of new N′-[N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)thiocarbamoyl]-2-[(1-aryl-1H-tetrazol-5-yl)sulfanyl]acetohydrazides 5a–5e were synthesized rapidly in high yields from 2-(1-aryl-1H-tetrazol-5-ylsulfanyl)acetohydrazides 3a–3e and 2,3,4-tri-O-acetyl-β-d-xylopyranosyl isothiocyanate 4, then 5a–5e were converted to a series of new 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-oxadiazole-2-amines 6a–6e and 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-thiadiazole-2-amines 7a–7e, respectively under mercuric acetate/alcohol system or acetic anhydride/phosphoric acid system, then deacetylated in the solution of CH₃ONa/CH₃OH. All of the novel compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The structures of compounds 2e, 3e, 5a and 5c have been determined by X-ray diffraction analysis. Some of the synthesized compounds displayed PTP1B inhibition and microorganism inhibition.     

A Simple Synthesis of N4 -(6-Aminohexyl)-2′-Deoxy-5′-O-(4,4′-Dimethoxytrityl)Cytidine

Abstract

The title compound was synthesized by a transamination reaction between N⁴ -benzoyl-2′-deoxy-5′-O-(4,4′-dimethoxytrityl)cytidine and hexane-1,6-diamine in the presence of 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD).     

O6-(4-Nitrophenyl)inosine and -Guanosine as Chromogenic Substrates for Adenosine Deaminase

Abstract

O⁶-(4-Nitrophenyl)inosine (la), O⁶ -(4-nitrophenyl)guanosine (1c) and O⁶ -(4-methylumbelliferonyl)inosine (2) were obtained by reaction of 6-chloro-9-(β-D-ribofuranosyl)purine (3a) or 2-amino-6-chloro-9-(β-D-ribofuranosyl)purine (3c) with sodium salts of 4-nitrophenol or 4-methylumbelliferone in N,N-dimethylformamide. Similarly, 6-chloro-9-(β-D-2,3-isopropylideneribofuranosyl)purine (3b) was transformed to 2′,3′-O-isopropylidene-O⁶-(4-nitrophenyl)inosine (1b). Deprotection of 1b with CF₃COOH gave compound la and O⁶ -(4-nitrophenyl)hypoxanthine (4). Compounds 1a and 1c are substrates for adenosine deaminase releasing 4-nitrophenol which is readily detected visually or spectrophotomemcally. Rate and extent of hydrolysis of la are significantly increased in the presence of purine nucleoside phosphorylase but xanthine oxidase has no influence. A potential fluorogenic analogue 2 is not a substrate for adenosine deaminase.

     

Synthesis of AZT analogues: 7-(3-azido-2hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-, 7-(3-triazolyl-2-hydroxypropyl)theophyllines

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph₃P/Py/NH₄OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N¹-propargyl thymine (6) afforded the regioisomeric triazole 7.     

Synthesis of (S)-2-fluoro- -daunosamine and (S)-2-fluoro- -ristosamine

Derivatives of (S)-2-fluoro- -daunosamine and (S)-2-fluoro- -ristosamine were synthesized, starting ultimately from 2-amino-2-deoxy- -glucose which was converted, according to the literature, into methyl 2-benzamido-4,6-O-benzylidene-2-deoxy-3-O-(methylsulfonyl)-α- -glucopyranoside (2). Treatment of 2 with tetrabutylammonium fluoride gave a 63% yield of (known) methyl 3-benzamido-4,6-O-benzylidene-2,3-dideoxy-2-fluoro-α- -altropyranoside (4), together with a 6% yield of its 2-benzamido-2,3-dideoxy-3-fluoro-α- -gluco isomer. From 4, the corresponding 6-bromo-2,3,6-trideoxyglycoside 4-benzoate (6) was obtained by Hanessian-Hullar reaction. Dehydrobromination of 6, followed by catalytic hydrogenation of the resulting 5-enoside, and subsequent debenzoylation and N-trifluoroacetylation, afforded the fluorodaunosaminide, methyl 2,3,6-trideoxy-2-fluoro-3-trifluoroacetamido-β- -galactopyranoside. Reductive debromination of 6, followed by debenzoylation and N-trifluoroacetylation, gave the fluororistosaminide, methyl 2,3,6-trideoxy-2-fluoro-3-trifluoroacetamido-α- -altropyranoside. The ¹H-n.m.r. spectra of the new aminofluoro sugars are discussed with respect to the effects of neighboring amino and acylamido substituents on geminal and vicinal ¹H–¹⁹F coupling constants, in comparison with the reported effects of oxyge substituents.     

Synthesis of Chlorodideoxynucleosides Using Tris(2,4,6-tribromophenoxy)-dichlorophosphorane (BDCP)

Abstract

5′-Chloro-5′-deoxy-N,3′-O-dibenzoylthymidine (3a), 5′-chloro-5′-deoxy-N⁴, 3′-O-dibenzoyldeoxycytidine(3b), 5′-chloro-5′-deoxy-N⁶,3′-O-dibenzoyldeoxyadenosine(3c), N-benzoyl-1-(3-chloro-2,3-dideoxy-5-O-trityl-ß-D-xylofuranosyl)thymine (5a) and N⁶-benzoyl-9-(3-chloro-2,3-dideoxy-5-O-trityl-ß-D-xylofuranosyl)adenine (5b) have been synthesized in very high yields using a new efficient reagent, tris(2,4,6-tribrom-ophenoxy)dichlorophosphorane (BDCP). The reaction time was greatly reduced to 5–8 min. NOE data suggested an inversion of configuration at C₃-position and thus an SN2 mechanism has been proposed for the chlorination reaction.

     

Synthesis of 3′-O2-(Azaheterocycle)-Thymidines

Abstract

The synthesis of 3′-O ²-(azaheterocycle)-thymidines is presented from 1-thia-3-aza-1,3-butadiene precursors (N-thioacylamidines). A variety of heterocycles is accessible using the dienic, the electrophilic or the nucleophilic reactivity of these thia-azabutadiene systems. 3′-O ²-(azaheterocycle)-thymidine analogues are regarded as potential substrates to interfere with the DNA-polymerization process.     

Synthesis of Base Substituted 2-Hydroxy-3-(purin-9-yl)-propanoic Acids and 4-(Purin-9-yl)-3-butenoic Acids

Abstract

Alkylation of 6-chloropurine and 2-amino-6-chloropurine with bromoacetaldehyde diethyl acetal afforded 6-chloro-9-(2,2-diethoxyethyl)purine (3a) and its 2-amino congener (3b). Treatment of compounds 3 with primary and secondary amines gave the N⁶-substituted adenines (5a–5c) and 2,6-diaminopurines (5d–5f). Hydrolysis of 3 resulted in hypoxanthine (6a) and guanine (6b) derivatives, while their reaction with thiourea led to 6-sulfanylpurine (7a) and 2-amino-6-sulfanylpurine (7b) compounds. Treatment with diluted acid followed by potassium cyanide treatment and acid hydrolysis afforded 6-substituted 3-(purin-9-yl)- and 3-(2-aminopurin-9-yl)-2-hydroxypropanoic acids (8–10). Reaction of compounds 3 with malonic acid in aqueous solution gave exclusively the product of isomerisation, 6-substituted 4-(purin-9-yl)-3-butenoic acids (15).     

The synthesis of oligosaccharide-asparagine compounds. V. O- -D-mannopyranosyl-(1 leads to 6)-O-(2-acetamido-2-deoxy- -D-glucopyranosyl)-(1 leads to 4)-2-acetamido-N-(L-aspart-4-oyl)-2-deoxy- -D-glucopyranosylamine

O-α-d-Mannopyranosyl-(1→6)-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-(1→4)-2-acetamido-N-(l-aspart-4-oyl)-2-deoxy-β-d-glucopyranosylamine (12), used in the synthesis of glycopeptides and as a reference compound in the structure elucidation of glycoproteins, was synthesized via condensation of 2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl bromide with 2-acetamido-4-O-(2-acetamido-3-O-acetyl-2-deoxy-β-d-glucopyranosyl)-3,6-di-O-acetyl-2-deoxy-β-d-glucopyranosyl azide (5) to give the intermediate, trisaccharide azide 7. [Compound 5 was obtained from the known 2-acetamido-4-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-3,6-di-O-acetyl-2-deoxy-β-d-glucopyranosyl azide by de-O-acetylation, condensation with benzaldehyde, acetylation, and removal of the benzylidene group.] The trisaccharide azide 6 was then acetylated, and the acetate reduced in the presence of Adams' catalyst. The resulting amine was condensed with 1-benzyl N-(benzyloxycarbonyl)-l-aspartate, and the O-acetyl, N-(benzyloxycarbonyl), and benzyl protective groups were removed, to give the title compound.     

A convenient route to synthesize N2-(isobutyryl)-9-(carboxymethyl)guanine for aeg-PNA backbone

Abstract

Synthesis of exclusive N²-(isobutyryl)-9-(carboxymethyl)guanine, an important moiety for peptide nucleic acid synthesis has been reported through a high-yielding reaction scheme starting from 6-chloro-2-amino purine. Crystal structures of two intermediates confirmed the formation of N9-regioisomer. This new synthetic route can potentially replace the conventional tedious method with moderate overall yield.     

Synthesis and crystal structure of a tetranuclear five-coordinated copper(II) complex with Schiff-base of N-(3-carboxylsalicylidene)-4-(2-iminoethyl)-morpholine

A tetranuclear copper(II) complex [Cu₄L₂(CH₃COO)₂(OH)₂]·6H₂O, in which L stands for the dianion of N-(3-carboxylsalicylidene)-4-(2-iminoethyl)morpholine, was synthesized and characterized by elemental analysis, IR, UV-Vis, TGA and X-ray single crystal diffraction. The crystal structure shows that the coordination unit is centrosymmetric with all the Cu(II) ions in square pyramidal coordination geometry. The coordination unit consists of two equivalent parts [Cu₂L(CH₃COO)(OH)], each containing two Cu(II) ions, a tetradentate N₂O₂ Schiff base dianion L²⁻, a CH₃COO⁻, and a OH⁻ anion. In [Cu₂L(CH₃COO)(OH)], the six coordination atoms (N₂O₄) are nearly coplanar, with Cu(1) and Cu(2) enchased in between; the phenolate oxygen and the OH⁻ oxygen as bridging atoms bind the two Cu(II) ions in close proximity; both O₄ around Cu(1) and N₂O₂ around Cu(2) form the basal plane of the coordination square pyramids. The two parts are connected by sharing two μ₃-OH⁻ oxygens and two μ₂-CH₃COO⁻ oxygens from each other, forming four edge-sharing coordination square pyramids around the four Cu(II) ions. A 3D network is formed through hydrogen bonding along a and c axis, and π-π interaction along b axis.     

1-(<Emphasis Type="Italic">N</Emphasis>-Trifluoroacetylamino)alkylphosphonic acids: synthesis and properties

Summary. The 1-(N-trifluoroacetylamino)alkylphosphonic acids (TFA-AA^P) – sub-products in the synthesis of O,O-dialkyl 1-(N-trifluoroacetylamino)alkylphosphonates and O,O-diethyl 1-aminoalkylphosphonates, were synthesized in two-stage transformations of 1-aminoalkylphosphonic acids including: trifluoroacetylation of 1-aminoalkylphosphonic acids (AA^P) using a trifluoroacetic anhydride/trifluoroacetic acid reagent (AA^P + TFAA/TFA→2) and subsequent hydrolysis of the intermediary compounds 2 into desired TFA-AA^P (2→TFA-AA^P). These intermediates 2 presented mixtures of the type of mixed anhydrides of TFAA and 1-(N-trifluoroacetylamino)alkylphosphonic, pyrophosphonic and polyphosphonic acids, which underwent rapid and quantitative conversion to corresponding TFA-AA^P during treatment with an excess of water. The title acids were isolated by direct evaporation of the corresponding post-reaction mixtures, and their physicochemical proprieties, including deacylation abilities, were determined. TFA-AA^P compounds can be re-converted into the starting amino acids AA^P under respectively mild conditions (AA^P→TFA-AA^P→AA^P).     

Convenient and Efficient Syntheses of Oligodeoxyribonucleotides Containing O 6-(Carboxymethyl)Guanine and O 6-(4-Oxo-4-(3-Pyridyl)Butyl)Guanine

O ⁶-(carboxymethyl)guanine (O ⁶-CMG) and O ⁶-(4-oxo-4-(3-pyridyl)butyl)guanine (O ⁶-pobG) are toxic lesions formed in DNA following exposure to alkylating agents. O ⁶-CMG results from exposure to nitrosated glycine or nitrosated bile acid conjugates and may be associated with diets rich in red meat. O ⁶-pobG lesions are derived from alkylating agents found in tobacco smoke. Efficient syntheses of oligodeoxyribonucleotides (ODNs) containing O ⁶-CMG and O ⁶-pobG are described that involve nucleophilic displacement by the appropriate alcohol on a common synthetic ODN containing the reactive base 2-amino-6-methylsulfonylpurine. ODNs containing O ⁶-pobG and O ⁶-CMG were found to be good substrates for the S. pombe alkyltransferase-like protein Atl1.

[Supplemental materials are available for this article. Go to the publisher's online edition of Nucleosides, Nucleotides & Nucleic Acids to view the free supplemental file.]     

Ribosylation of the Base Residue of Inosine Derivatives by Phase-Transfer Catalysis

Abstract

Reaction of 2′,3′,5′-O-silylated inosine derivative 1 with 2, 3-O-isopropylidene-5-O-tritylribosyl chloride (3) in a two-phase (CH₂Cl₂-aq. NaOH) system in the presence of Bu₄NBr gave three products, i. e., 6-O-α-, 6-O-β-, and N ¹-β-isomers of glycosides 4, 5a, and 5b. A similar PTC reaction of 1 with 2, 3, 5-tri-O-benzylribosyl bromide (9) gave four regio- and stereo-isomers involving the N¹-β-glycoside 10. Reaction of 1 with 2, 3, 5-tri-O-benzoylribosyl bromide (11) afforded three products involving the desired N¹-β-glycoside 12b, which could be deprotected to give N ¹-ribosylinosine (15b) as a useful intermediate for the synthesis of cIDPR.

     

Facile Synthesis of N-(1-Alkenyl) Derivatives of 2,4-Pyrimidinediones

Abstract

N-(1-alkenyl) derivatives of 2,4-pyrimidinediones (6–9) were prepared in a one pot synthesis from aldehydes and the nucleobases using trimethylsilyl trifluoromethanesulfonate (TfOTMS) as coupling reagent. Presilylation of the above nucleobases, and N ⁶-benzoyladenine, with excess N,O-bis(trimethylsilyl)acetamide (BSA) followed by addition of one mol eq. TfOTMS yielded the N-(1-trimethylsilyloxyalkyl) derivatives 1–5.     

Synthesis of 1,5-Anhydro-2-(N 6-Cyclopentyladenin-9-Yl)-2-Deoxy-D-Altrohexitol

Abstract

The N ⁶-cyclopentyladenosine (CPA) analogue (4) was synthesized in 10 steps starting from glucose. The results of the radioligand binding assays are consistent with the thus far published findings that compounds containing a six-membered moiety at N ⁹ exhibit extremely weak affinity for adenosine receptors. Replacement of the ribofuranosyl moiety of CPA (2) by a 2-deoxy-D-altrohexitol moiety is sufficient to completely abolish its agonist activity.     

Identification,characterization and in vitro neuroprotection of N6-(4-hydroxybenzyl) adenine riboside and its metabolites

N⁶-(4-hydroxybenzyl) adenine riboside (NHBA), isolated from Gastrodia elata Blume, has been demonstrated to show great pharmacological effects. The present study aimed to synthesize and identify the metabolites of NHBA, and to determine their neuroprotective potentials in vitro. After incubation with rat liver microsomes in the presence of NADPH, two metabolites were detected, which were further semisynthesized and identified as N⁶-(4-hydroxylbenzyl) purine (NHBP) and N⁶-(3,4-dihydroxylbenzyl) adenine riboside (ONHBA) by UPLC-QTOF-MS, ¹H NMR and ¹³C NMR. Furthermore, the neuroprotective activities of NHBA and two metabolites were evaluated in SH-SY5Y cells. Our results demonstrated that NHBA substantially protected against H₂O₂-induced neuronal death in SH-SY5Y cells. Moreover, both ONHBA and NHBP could significantly prevent Aβ oligomers- and H₂O₂-induced neuronal death in SH-SY5Y cells. These results suggested that NHBA and its metabolites, ONHBA and NHBP, might be suitable for the development of new drugs in the treatment of neurodegenerative diseases, including Alzheimer’s disease in particular.     

Synthesis of methyl O-(3-deoxy-3-fluoro-β- -galactopyranosyl)-(1→6)-β- -galactopyranoside and methyl O-(3-deoxy-3-fluoro-β- -galactopyranosyl)-(1→6)-O-β- -galactopyranosyl-(1→6)-β- -galactopyranoside

Condensation of 2,4,6-tri-O-acetyl-3-deoxy-3-fluoro-α- -galactopyranosyl bromide (3) with methyl 2,3,4-tri-O-acetyl-β- -galactopyranoside (4) gave a fully acetylated (1→6)-β- -galactobiose fluorinated at the 3′-position which was deacetylated to give the title disaccharide. The corresponding trisaccharide was obtained by reaction of 4 with 2,3,4-tri-O-acetyl-6-O-chloroacetyl-α- -galactopyranosyl bromide (5), dechloroacetylation of the formed methyl O-(2,3,4-tri-O-acetyl-6-O-chloroacetyl-β- -galactopyranosyl)-(1→6)- 2,3,4-tri-O-acetyl-β- -galactopyranoside to give methyl O-(2,3,4-tri-O-acetyl-β- -galactopyranosyl)-(1→6)-2,3,4-tri-O-acetyl-β- -galactopyranoside (14), condensation with 3, and deacetylation. Dechloroacetylation of methyl O-(2,3,4-tri-O-acetyl-6-O-chloroacetyl-β- -galactopyranosyl)-(1→6)-O-(2,3,4-tri-O-acetyl- β- -galactopyranosyl)-(1→6)-2,3,4-tri-O-acetyl-β- -galactopyranoside, obtained by condensation of disaccharide 14 with bromide 5, was accompanied by extensive acetyl migration giving a mixture of products. These were deacetylated to give, crystalline for the first time, the methyl β-glycoside of (1→6)-β- -galactotriose in high yield. The structures of the target compounds were confirmed by 500-MHz, 2D, ¹H- and conventional ¹³C- and ¹⁹F-n.m.r. spectroscopy.     

Stereoselective Reactions OF 1-(4,6-O-Benzylidene-2,3-Didehydro-2,3-dideoxy-3-nitro-β-D-hexopyranosyl)uracil with some Nucleophiles¶

Abstract

Michael addition of benzylamine, piperidine, morpholine, pyrrolidine, cyclohexylamine, allylamine and dimethylmalonate to the nitroolefin (5) generated in situ from 1-(4,6-O-benzylidene-3-deoxy-3-nitro-β-D-glucopyranosyl)uracil (4b) gave the corresponding 2-(substituted-amino)-3-deoxy-3-nitro-β-D-glucopyranosides (6a-f and 6h). Reaction of 4b with N,N-carbonyldiimidazole directly gave 6g. Compound 4b was converted into the 2-deoxy analogue (8), which was reduced to the 3-amino (9) and 3-hydroxylamino analogue (10).