New route for the synthesis of 2-thiouracil analogues of 3′-azido-2′,3′-dideoxy nucleosides

Summary Reaction of 3-azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-D-erythro-pentofuranoside (5) with silylated 2-thiouracil and 5-alkoxy-2-thiouracils in the presence of trimethylsilyl trifluoromethanesulfonate afforded an anomeric mixture of the corresponding 3-azido-2,3-dideoxy-2-thiouridine derivatives with the -anomer as the main product. Deprotected nucleosides were obtained by treatment with tetrabutylammonium fluoride.

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Ein neuer Weg zur Synthese von 2-Thiouracil-Analogen von 3-Azido-2,3-dideoxy-Nucleosiden

Zusammenfassung Die Reaktion von 3-Azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-D-erythro-pentofuranosid (5) mit silyliertem 2-Thiouracil und 5-Alkoxy-2-thiouracil in Gegenwart von Trimethylsilyltrifluormethansulfonat ergab eine anomere Mischung der entsprechenden 3-Azido-2,3-dideoxy-2-thiouridin-Derivate, wobei das -Anomer das Hauptprodukt darstellte. Die ungeschützten Nucleoside wurden mittels Behandlung mit Tetrabutylammoniumfluorid erhalten.

     

Electronic structure and electro-optical properties of ion radicals formed during the reduction of N,N′-dialkylsubstituted salts of 4,4′-bipyridyl

Symmetric N,N′-disubstituted salts of 4,4′-bipyridyl (viologens) are synthesized and described. It is shown by cyclic voltammetry that disubstituted salts of 4,4′-bipyridyl have a tendency toward reversible two-electron reduction. Normal first and second step oxidation-reduction potentials with respect to saturated silver chloride electrodes at various potential scan rates are found. The spectra of the high-resolution electron paramagnetic resonance of viologen cation radicals formed during the reduction of N,N′-disubstituted salts of 4,4′-bipyridyl are obtained and interpreted. It is established that the nature of substitutes and counterions in a viologen molecule considerably influences the distribution of its spin density, voltammetric curves, and electro-optical properties.     

Is NO3 formed during the decomposition of nitramine explosives?

Quantum chemistry calculations reveal that it is both thermodynamically and kinetically feasible for NO2 to be oxidized by RDX (1,3,5-trinitrohexahydro-s-triazine) or its initial decomposition products. Thus, NO3 (nitrate radical) may be produced during the thermal decomposition of RDX and other nitramines. However, experimental studies of the gaseous products, by mass spectrometry and microwave spectroscopy, have never detected NO3. This fact is reconciled with the calculations by noting that (1) the electron-impact, positive-ion mass spectrum of NO3 shows little parent ion, (2) NO3 lacks a permanent electric dipole moment and is therefore invisible to microwave spectroscopy, and (3) NO3 is quite reactive. Further experiments are encouraged and could lead to a new method for detecting concealed nitramines.     

Mechanism of Formation of Ribonucleoside Cyclic 2′,3′-Phosphates in the Reaction of Appropriate 3′,5′-Phos-Phorothioates with Epoxides

Abstract

It has been recently demonstrated in our laboratory CD that ribonucleoside cyclic 3′,5′-phosphorothioates react with epoxides to give as a major product corresponding cyclic 5′,3′-phosphates, We now report the results OF our ste-reochemical studies OF this reaction. WE have Found that the diastereomerically pure (Sp) 3′.5′-CUFLPS when treated with styrene [¹⁰O]-oxide in ethanol gives the same isotopomer OF 2′,3′-[¹⁰O]cUMP as that obtained From the reaction of endo-2′.3′-cUMPS with styrene [¹⁰O]-oxide. This result strongly supports our previous assumption that reaction of 3′,5′-cNMPS with epoxides proceeds via 3′-oxathiaphosphorylated intermediate (L) which is Formed with inversion and decomposes to 2′,3′-cNMP with retention of configuration at phosphorus atom.     

Amperometric Immunosensor for the Determination of 2′,3′-dideoxyinosine

Abstract

An amperometric immunosensor, based on carbon paste impregnated with solubilized antidideoxyinosine (from rabbit lyophilized powder, whole antiserum) has been constructed for the assay of anti-HIV agent dideoxyinosine (didanosine, DDI). The amperometric immunosensor was reliably used for dideoxyinosine assay in the 900 pmol/L to 9 nmol/L concentration range, with a detection limit of 180 pmol/L, at E = +1.04 V vs. Ag/AgCl. The construction of the immunosensor is reproducible. Its surface can be easily renewed by simple polishing on an aluminium paper. The new amperometric immunosensor is reliable for the assay of 2′,3′-dideoxyinosine in raw material as well as in its pharmaceutical formulation (Videx tablets).     

Transformations of β-d-xylofuranosyl nucleosides. Synthesis of 3′-azido-3′-deoxythymidine

A modified synthesis of 3′-azido-3′-deoxythymidine starting fromD-xylose is proposed. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2062–2063, October, 1998.     

Investigations in the region of 2,3′-biquinolyl 4. Alkylation of the dianion of 2,3′-biquinolyl

With alkyl chlorides and alkyl phenyl ethers the dianion of 2,3-biquinolyl forms the products from alkylation at position 4. Their treatment with alkyl halides or water gives 1, 4-dialkyl-1, 4-dihydro-2,3-biquinolyls or 4-alkyl-1,4-dihydro-2,3-biquinolyls respectively.For communication 3, see [1].Stavropol State University, Stavropol, Russia 355009. Russian Chemical Technology University, Moscow 125190. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1214–1217, September, 1998.     

An Efficient Procedure for the Preparation of 3′-Acetyl-2′,3′-dihydrobenzothiazoles by Ring Contraction of 2′,3′-Dihydro-1,5-Benzothiazepines Under Acetylating Conditions

Reaction of 2-benzoyl-6-hydroxy-3-methyl-5-(2′-substituted-2′,3′-dihydro-1,5-benzothiazein-4′-yl) benzofurans (4a-f) with a mixture of acetic anhydride and pyridine afforded 6-acetoxy-2-benzoyl-3-methyl-5-(3′-acetyl-2′-substitutedstyryl-2′,3′-dihydrobenzothiazole-2′-yl) benzofurans (5a-f) as sole products in good yields. A reaction mechanism for the ring contraction is proposed. All the compounds (5a-f) were screened for their antifeedant activity by the “Non-Choice test method” using 6 h prestarved fourth instar larvae of Spodoptera litura F. Compounds 5a, 5c and 5d exhibited highest antifeedant activity.     

Synthesis of 3′-deoxy-3′-iminodiacetic acid and 3′-deoxy-3′-aminodiethanol thymidine analogues and NMR study of their complexation with boronic acids

The iminodiacetic acid and aminodiethanol moieties are known for their ability to generate with boronic acids bicyclic structures having a strong intramolecular NB coordination. We describe here the convergent synthesis of 3′-deoxy-3′-iminodiacetic acid and 3′-deoxy-3′-aminodiethanol thymidine analogues. The abilities of these compounds to form boronate complexes with aliphatic or aromatic boronic acids were established by 1D and 2D ¹H and ¹³C NMR. Moreover, conformational analysis of the newly synthesized compounds revealed a marked preference for an N-type sugar puckering.     

Theoretical study on the hydrolysis mechanism of N,N-dimethyl-N′-(2′,3′-dideoxy-3′-thiacytidine)formamidine

The hydrolysis mechanisms of N,N-dimethyl-N′-(2′,3′-dideoxy-3′-thiacytidine)formamidine (FA-3TC) in the gas phase and in aqueous solution were studied by use of the density functional theory B3LYP/6-31 G(d, p) method. Two possible reaction pathways in the title reaction were considered. In one pathway water attacks the C=N double bond first (path A) while in the other water attacks the C—N single bond first (path B). The calculated results indicate that the first step in both pathways is the rate-limiting process and path A is more favorable than path B in the gas phase. The effect of solvent water on the title reaction was assessed at the B3LYP/6-31 G(d, p) level of theory based on the po-larizable continuum model (CPCM). In water the first mechanism (path A) is also favored.     

Toward the synthesis of 1′E-isomer of ent-hyptenolide

A short total synthesis of a diacetoxylated E,E-diene lactone ent-hyptenolide, was achieved involving from Phosphonate and cis-butene 1,4-diol. Brown Asymmetric allylation, Acrylation, Acetylation, Ring-closing metathesis as the key steps has been described. Moreover, the biological activity of ent-hyptenolide was evaluated on HeLa, A549, IMR32, and MDA-MB231 cancer cell lines. The ent-hyptenolide selectively and potently inhibited the growth of IMR32 cell line.     

Conformational Properties of the Phosphate Rings of Neutral Phosphoramidate Derivatives of Ribo- and 2′-Deoxyribonucleoside Cyclic 3′,5′-Monophosphates

Abstract

An investigation of the effects of changing the nature of X, nitrogen base (B), and amino substituent (R₂N) on the equilibrium 1?2 was carried out.

The influence of the above structural changes on the time-averaged coupling constants J_AP and J_BP, determined at 300 MHz, were used to follow changes in K_eq. With constant R₂N, small effects from variation of X and B were found. A large range in K_eq arose from changes in the steric size of R₂N. These results will be related to the question of the ease of chair to twist interconversion of the phosphate ring essential to the biological activities of the naturally occurring diesters, cAMP and cGMP.     

In situ observation of the pressure-induced mesophase for 4′-n-hexadecyloxy-3′-nitrobiphenyl-4-carboxylic acid

In situ observation of the optical texture, and X-ray patterns of the pressure-induced mesophase seen for 4′-n-hexadecyloxy-3′-nitrobiphenyl-4-carboxylic acid (ANBC-16) was performed under hydrostatic pressures up to 100MPa using a polarizing optical microscope equipped with a high pressure hot stage and a wide angle X-ray diffractometer equipped with a high pressure vessel respectively. It was found that the pressure-induced mesophase (hereafter refered to as ‘X’) appeared at pressures above 60 MPa, and exhibits a birefringent broken-fan or a sand-like texture that remain unaltered in the SmC phase. The POM-transmitted light intensity curve measured on heating clearly showed the Cr₄ → Cr₁ → SmC → ‘X’ → SmA → I transition sequence at 80 MPa. The optical texture and the POM-transmitted light intensity measured during a pressure cycle at 185°C showed a reversible change between the cubic and ‘X’ phases. The WAXD pattern of the ‘X’ phase showed a spot-like pattern, suggesting no layered structure for this phase, and also revealed a substantial decrease in the d-spacing of the low angle reflection at 80 and 100 MPa, compared with the d-spacings of the (0 0 1) reflection of the SmC phase and also the (2 1 1) reflection of the cubic phase. It is concluded from these data that the ‘X’ phase is a birefringent hexagonal columnar phase.     

Investigation of reactions postulated to occur during inhibition of ribonucleotide reductases by 2′-azido-2′-deoxynucleotides

Model 3′-azido-3′-deoxynucleosides with thiol or vicinal dithiol substituents at C2′ or C5′ were synthesized to study reactions postulated to occur during inhibition of ribonucleotide reductases by 2′-azido-2′-deoxynucleotides. Esterification of 5′-(tert-butyldiphenylsilyl)-3′-azido-3′-deoxyadenosine and 3′-azido-3′-deoxythymidine (AZT) with 2,3-S-isopropylidene-2,3-dimercaptopropanoic acid or N-Boc-S-trityl-L-cysteine and deprotection gave 3′-azido-3′-deoxy-2′-O-(2,3-dimercaptopropanoyl or cysteinyl)adenosine and the 3′-azido-3′-deoxy-5′-O-(2,3-dimercaptopropanoyl or cysteinyl)thymidine analogs. Density functional calculations predicted that intramolecular reactions between generated thiyl radicals and an azido group on such model compounds would be exothermic by 33.6–41.2 kcal/mol and have low energy barriers of 10.4–13.5 kcal/mol. Reduction of the azido group occurred to give 3′-amino-3′-deoxythymidine, which was postulated to occur with thiyl radicals generated by treatment of 3′-azido-3′-deoxy-5′-O-(2,3-dimercaptopropanoyl)thymidine with 2,2′-azobis-(2-methyl-2-propionamidine) dihydrochloride. Gamma radiolysis of N₂O-saturated aqueous solutions of AZT and cysteine produced 3′-amino-3′-deoxythymidine and thymine most likely by both radical and ionic processes.     

Synthesis of 2-O-ethyl analogues of 3′-azido- and 3′-fluoro-2′,3′-dideoxyuridines and evaluation of their biological activity against HIV

Summary 2-O-Ethyluracil and 2-O-ethylthymine were silylated with 1,1,1,3,3,3-hexamethyldisilazane and condensed in the presence ofTMS triflate with 2,3-dideoxy-3-fluoro-D-erythro-pentofuranoside, 3-azido-2,3-dideoxy-D-erythro-pentofuranoside, and 2,3-dideoxy-3-phthalimido--D-erythro-pentofuranose derivatives to give the corresponding 2-O-ethyl nucleosides. Deprotection with saturated methanolic ammonia afforded the 2,3-dideoxy-3-fluoro-2-O-ethyluridines, whereas 3-azido-2,3-dideoxy-3-O-ethyluridine was obtained by deprotection with tetrabutylammonium fluoride in tetrahydrofuran. 3-Amino-2,3-dideoxy-3-O-ethyluridine could be obtained only by treatment of the corresponding 3-azido nucleoside with triphenylphosphine in pyridine. 3-Deoxy-2-O-ethyl-3-fluorothymidine (6b) showed moderate activity against HIV-1.

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Synthese von 2-O-Ethyl-Analogen von 3-Azido- und 3-Fluor-23-dideoxyuridinen und Bestimmung ihrer biologischen Aktivität gegenüber HIV

Zusammenfassung 2-O-Ethyluracil und 2-O-Ethylthymin wurden mit 1,1,1,3,3,3-Hexamethyldisilazan silyliert und in Gegenwart vonTMS-triflat mit 2,3-Dideoxy-3-fluoro-D-erythro-pentofuranosid, 3-Azido-2,3-dideoxy-D-erythro-pentofuranosid und 2,3-Dideoxy-3-phthalimido--D-erythro-pentofuranosederivaten zu den entsprechenden 2-O-Ethyl-Nucleosiden umgesetzt. Entfernung der Schutzgruppe mit gesättigter methanolischer Ammoniaklösung lieferte 2,3-Dideoxy-3-fluor-2-O-ethyluridin; 3-Azido-2,3-dideoxy-3-O-ethyl-uridin wurde durch Entschützung mit Tetrabutylammoniumfluorid in Tetrahydrofuran erhalten. 3-Amino-2,3-dideoxy-3-O-ethyl-uridin konnte nur durch Behandeln des entsprechenden 3-Azido-Nucleosids mit Triphenylphosphin in Pyridin hergestellt werden. 3-Deoxy-2-O-ethyl-3-fluor-thymidin (6b) zeigt geringe Aktivität gegenüber HIV-1.

     

Investigation of the By-products Formed during the Catalytic Synthesis of 4,4＇-Methylenedimethyldiphenylcarbamate

The structures of the by-products formed during the catalytic synthesis of 4,4＇-methyldiphenylcarbamate （MDC） by the reaction of 4,4＇-methylenedianiline （MDA） with dimethyl carbonate （DMC） were identified and then the mechanisms of their formation were proposed.     

Synthesis of β-L-2′,3′-Dideoxy-2′-fluoro-3′-hydroxymethylarabinofuranosyl Pyrimidine Nucleosides

β-2′,3′-Dideoxy-2′-fluoro-3′-hydroxymethylarabinofuranosylthymine 10 and cytosine 12 were synthesized from L-xylose and were found to be inactive against HIV-1 in acutely infected lymphocytes.