Ahmed A. El-Barbary

Synthesis and evaluation of antiviral activity of 2′-deoxyuridines with 5-methylene-2-thiohydantoin substituents in the 5-position

Summary1-(2-Deoxy-3,5-bis-O-(4-methylbenzoyl)-D-erythro-pentofuranosyl)-5-formyluracil (4) was synthesized from 5-formyluracil and an appropriate methyl glycoside and condensed with 2-thiohydantoin (5a) and its corresponding 3-phenyl derivative5b to give 5-[1-(2-deoxy-3,5-bis-O-(4-methylbenzoyl)-D-erythro-pentofuranosyl)uracil-5-ylmethylene]-2-thiohydantoins7a and7b, respectively, in 65–70% yield. They were deprotected with sodium methoxide in methanol to give both anomers of the free nucleosides. In a different route 5-formyluracil (1) was condensed with5b and subsequently with an appropriate methyl glycoside to give7b.Zusammenfassung1-(2-Deoxy-3,5-bis-O-(4-methylbenzoyl)-D-erythro-pentofuranosyl)-5-formyluracil (4) wurde aus 5-Formylurazil und dem entsprechenden Methylglycosid synthetisiert und mit 2-Thiohydantoin (5a) und seinem 3-Phenylderivat5b kondensiert, wobei die 5-[1-(2-Deoxy-3,5-bis-O-(4-methylbenzoyl)-D-erythro-pentofuranosyl)uracil-5-ylmethylene]-2-thiohydantoine7a bzw.7b in 65–70% Ausbeute erhalten wurden. Nach Entfernung der Schutzgruppen mit Natriummethoxid in Methanol erhielt man beide Anomeren der freien Nucleoside. Auf einem anderen Weg wurde 5-Formyluracil (1) mit5b und anschließend mit einem entsprechenden Methylglycosid zu7b kondensiert.

SYNTHESIS OF SOME NEW 4-AMINO-1,2,4-TRIAZOLE DERIVATIVES AS POTENTIAL ANTI-HIV AND ANTI-HBV

Some novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazolylisoindole-1,3-dione 2a–c were prepared by heating 4-amino-5-aryl-1,2,4-triazole-3-thiones 1a–c with different (1,3-dioxo-1,3-dihydro-isoindol-2-yl) carboxylic acids in POCl3. Compounds 2a, b were hydrolyzed using HCl to yield [1,2,4]triazolo[3,4-b][1,3,4]thiadiazolyl-alkylamines 3a, b. Coupling 1a, c with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (ABG) afforded the corresponding S-glucosides 4a, b, which on oxidation with KMnO4 gave the corresponding sulfone 5. Treatment 1b, c with diphenyl diazomethane afforded benzhydrylsulfanyltriazolylamines 7a, b. 1,8-Bis-(4-chloro-phenyl)-bis[1,2,4]triazolo[3,4-c-,4′,3′-e][1,2,4,5]dithiadiazine 8 was formed by oxidation of 1b with lead tetracetate. Compound 1c reacted with morpholine in the presence of KI and I2 to give the triazolodisulfide 9 .

Synthesis of 3′-Amino and 5′-Amino Hydantoin 2′-Deoxynucleosides

Abstract 3′-Amino and 5′-amino derivatives of hydantoin 2′-deoxynucleosides have been prepared from the corresponding 3′-phthalimido and 5′-azido nucleosides, respectively, which in turn were prepared by condensation of appropriate sugars with 5-benzylidenehydantoin. The amino nucleosides were tested for their potential activity against HIV and HSV.

Convergent synthesis of 2′,3′-dideoxy-3′-methylthio and 2′,3′-dideoxy-3′-mercapto nucleosides and their disulfide analogues — Potential anti-HIV agents

SummaryThe iodide4(α) or7 synthesized in three steps from 2-deoxy-D-ribose1, has been subjected to a number of nucleophilic substitution reactions producing the 3-benzoylthio-, 3-methylthio- and the 3-thiocyanato-2,3-dideoxy-D-erythro-pentofuranosides8,13 and15, respectively, in addition to the disulfide17 of their 3-mercapto analogue. Subjecting the thiobenzoate8 to the Friedel-Crafts catalyzed silyl Hilbert Johnson reaction in conjunction with the silylated nucleobases of uracil, thymine and N4-isobutyrylcytosine9a–c resulted in the isolation of the 2′,3′-dideoxy-3′-mercapto nucleosides11 and their disulfides12 subsequent to deprotection. The 2,3-dideoxy-3-methylthio-pentofuranoside13 afforded both anomers of the 2′,3′-dideoxy-3′-methylthio nucleosides19 and20 under similar conditions. The first known example of a coupling directly on a 2,3-didehydro-2,3-dideoxyfuranose is presented. 2′,3′-Dideoxy-3′-mercaptocytidine showed protection against HIV-1 in MT-4 cells with ED50=20 µM.ZusammenfassungDie in drei Stufen aus 2-Desoxy-D-ribose hergestellten Jodide4(α) bzw. 7 wurden einer Reihe von nucleophilen Substitutionsreaktionen unterzogen, wobei die 3-Benzoylthio-, 3-Methylthio-und 3-Thiocyanato-2,3-didesoxy-D-erythro-pentofuranoside8,13 und15 zusätzlich zum Disulfid17 ihrer 3-Mercapto-Analogen entstanden. Bei der Friedel-Crafts-katalysierten Silyl-Hilbert-Johnson Reaktion des Thiobenzoats8 in Verbindung mit den silylierten Nucleobasen Uracil, Thymin und N4-Isobutyrylcytosin9a–c entstanden nach der Schutzgruppenentfernung die 2′,3′-Didesoxy-3′-mercapto-Nucleoside11 und ihre Disulfide12. Unter ähnlichen Bedingungen ergaben die 2′,3′-Didesoxy-3′-methylthiopentofuranoside13 beide Anomere der 2′,3′-Didesoxy-3′-methylthionucleoside19 und20. Es wird das erste Beispiel einer direkten Kopplung 2,3-Didehydro-2,3-didesoxyfuranose vorgestellt. 2′,3′-Didesoxy-3′-mercaptocytidin zeigte Schutzwirkung gegenüber HIV-1 in MT-4 Zellen mit ED50=20 µM.

Synthesis of 5′-amino- and 5′-azido-2′,5′-dideoxy nucleosides from thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

SummaryThieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (4) was silylated and condensed with methyl 5-azido-2,5-dideoxy-3-O-(4-methylbenzoyl)-D-erythro-pentofuranoside (2) in the presence ofTMS triflate to afford the corresponding protected nucleoside6 and acyclic nucleoside7. Deprotection of6 with MeONa/MeOH at room temperature gave 1-(5-azido-2,5-dideoxy-α-D-erythro-pentofuranosyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (8) and the corresponding β anomer9, whereas compound7 yielded 5-azido-2,5-dideoxy-1-(2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-1-yl)-1-O-methyl-D-erythro-pentitol (10) under the same reaction conditions. 1-(5-Amino-2,5-dideoxy-β-D-erythro-pentofuranosyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (11) was obtained on treating9 with Ph3P in pyridine followed by hyrolysis with NH4OH. The anomeric nucleosides14 and15 and the corresponding acyclic nucleoside16 were obtained when4 was trimethylsilylated and condensed with methyl 2-deoxy-3,5-di-O-(4-methylbenzoyl)-D-erythro-pentofuranoside (3) followed by deprotection with MeONa in MeOH. Compounds8 and9 were also obtained when the anomeric mixture14/15 was treated with a mixture of NaN3, Ph3P, and CBr4 in dryDMF at room temperature.ZusammenfassungDie Silylierung und anschließende Kondensation von Thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion (4) mit 5-Azido-2,5-dideoxy-3-O-(4-methylbenzoyl)-D-erythro-pentofuranosid (2) in Gegenwart vonTMS-Triflat führt zum entsprechenden geschützten Nucleosid6 und zum acyclischen Nucleosid7. Abspaltung der Schutzgruppe von6 mit MeONa/MeOH bei Zimmertemperatur lieferte 1-(5-Azido-2,5-dideoxy-α-D-erythro-pentafuranosyl)-thieno[2,3-d]pyrimidin-2,4(1H,3H)-dion (8) und das entsprechende β-Anomere9, während Verbindung7 unter den gleichen Reaktionsbedingungen 5-Azido-2,5-dideoxy-1-(2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-1-yl)-1-O-methyl-D-erythro-pentitol (10) ergab. Umsetzung von9 mit Ph3P in Pyridin und anschließende Hydrolyse mit NH4OH führte zu 1-(5-Amino-2,5-dideoxy-β-D-erythro-pentafuranosyl)thieno[2,3-d]pyrimidin-2,4-(1H,3H)-dion (11). Die anomeren Nucleoside14 und15 und das entsprechende acyclische Nucleosid16 wurden durch Trimethylsilylierung und Kondensation von4 mit 2-Deoxy-3,5-di-O-(4-methylbenzoyl)-D-erythro-pentofuranosid (3) sowie anschlieβende Entfernung der Schutzgruppe mit MeONa in MeOH hergestellt. Die Verbindungen8 und9 wurden auch durch Behandeln des anomeren Gemisches14/15 mit einer Mischung von NaN3, Ph3P und CBr4 in trockenemDMF bei Zimmertemperatur erhalten.

Convergent synthesis of 2′,3′-dideoxy-3′-mercapto nucleosides — Potential anti-HIV agents

SummaryMethyl 3-benzoylthio-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-β-D-erythro-pentofuranoside (4) and its corresponding α anomer5 were synthesized in four steps from 2-deoxy-D-ribose and used as substrates for the synthesis of nucleosides by condensation with silylated thymidine and N6-isobutyryladenine. The nucleosides were deprotected by treatment with Bu4NF inTHF followed by reaction with MeONa in MeOH to give 3′-deoxy-3′-mercaptothymidine (8), 2′,3′-dideoxy-3′-mercaptoadenosine (15) and its corresponding α anomer16. In the latter reactions it was important to use degassed solvents to minimize formation of the corresponding disulfides of purine nucleosides. Using Bu4NF, without subsequent reaction with MeONa in the deprotection reaction, resulted in intermolecular transesterification reactions.ZusammenfassungMethyl-3-benzoylthio-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-β-Derythro-pentofuransoid (4) und sein entsprechendes α-Anomeres wurden in vier Stufen, ausgehend von 2-Deoxy-D-ribose, hergestellt und als Substrat für die Synthese von Nucleosiden durch Kondensation mit silyliertem Thymidin und N6-Isobutyryladenin verwendet. Die Nucleoside wurden durch Behandeln mit Bu4NF inTHF und anschließende Reaktion mit MeONa in MeOH zu 3′-Deoxy-3′-mercaptothymidin (8), 2′,3′-Dideoxy-3′-mercaptoadenosin (15) und seinem entsprechenden α-Anomeren16 entschützt. Bei letzterer Reaktion war die Verwendung von entgasten Lösungsmitteln wesentlich, um die Bildung der entsprechenden Disulfide der Purinnucleoside hintanzuhalten. Die Verwendung von Bu4NF ohne anschließende Reaktion mit MeONa bei der Abspaltung der Schutzgruppen führte zu intermolekularen Umesterungen.