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A new intercalating nucleic acid monomer Y was obtained via alkylation of pyren-1-ol with (S)-(+)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol under Mitsunobu conditions followed by hydrolysis with 80% aqueous acetic acid to give a diol which was tritylated with 4,4′-dimethoxytrityl chloride followed by treatment with 2-cyanoethyltetraisopropylphosphordiamidite in the presence of N,N′-diisopropylammonium tetrazolide. In this way the monomer Y was obtained as its dimethoxytrityl-protected phosphoramidite building block for standard DNA synthesis. The corresponding oligonucleotides from Y have nearly identical hybridization properties with those of intercalating nucleic acid (INA) where neighboring oxygen and carbon atoms are interchanged in the linker. The synthesis of monomer Y avoids the use of allergic intermediates which are a problem in the synthesis of INA.

Treatment of 3′-amino-3′-deoxythymidine (1) with carboxylic acid anhydrides afforded the corresponding acylamino derivatives 2a–f. Reaction of 1 with a variety of isothiocyanates led to the corresponding thioureido derivatives 3a–i. Also, conversion of 1 into 3′-carbylamino-3′-deoxythymidine (7) is reported. The compounds 2, 3, and 8 were evaluated for their anti-HIV activity in MT-4 cells, but did not show sufficient efficacy. Synthese N-substituierter 3′-Amino-3′-desoxythymidin-Derivate und ihre biologische Prufung gegen HIV Umsetzung von 3′-Amino-3′-desoxythymidin (1) mit Carbonsaureanhydriden fuhrt zu den entspr. Acylamin-Derivaten 2a–f. Aus 1 und verschiedenen Isothiocyanaten entstehen die Thioharnstoffe 3a–i. Auch die Herstellung des Isonitrils 7 wird beschrieben. Die Verbindungen 2, 3 und 8 wurden auf Aktivitat gegen HIV gepruft, sie erwiesen sich jedoch als nicht ausreichend wirksam.

A modified synthesis of protected 2,3-dideoxyribose5 starting fromL-glutamic acid (1) is described. Reaction of5 with silylated 5-hydroxymethyluracil7 a and 5-alkoxymethyluracils7 b–e in the presence of trimethylsilyl triflate afforded an anomeric mixture of 2′,3′-dideoxyuridine derivatives8 a–e and9 a–e. Deprotection with methanolic ammonia and separation by chromatography gave the corresponding nucleosides10 a–e and11 a–e. Treatment of9 b–e with tri(1H-1,2,4-triazol-1-yl)phosphine oxide and subsequent reaction of12 b–e with ammonia in dioxane afforded the cytosine derivatives13 b–e which on treatment with methanolic ammonia gave the corresponding 2′,3′-dideoxycytidine derivatives14 b–e and15 b–e. In contrast with the parent compounds, these alkoxymethyl derivatives had no appreciable activity against human immunodeficiency virus (HIV-1).

The 5-OH-protected methyl glycosides 2 and 3 were epimerized to give the corresponding epimers 6 and 7 via an oxidation-reduction procedure. Reaction of 6 with diethylamino-sulfur trifluoride (DAST) afforded the fluoro sugar 8, which was coupled with thymine to give 3′-deoxy-3′-fluorothymidine (12) after deprotection with saturated ammonia in methanol.

(2E,4S)-5-Acetoxy-4-formyloxy-2-pentenal (2) prepared in one step from tri-O-acetyl-D-glucal was selectively deformylated to give an α,β-unsaturated aldehyde 3 with an unprotected hydroxy group at C-4. Michael-type addition reaction of hydrazoic acid to 3 followed by acylation at C-1 gave a 1:1 mixture of the erythro- and threo-isomers of 5-O-acetyl-3-azido-1-O-(4-biphenylcarbonyl)-2,3-dideoxypentofuranoses 4 and 5. They were used as substrates for nucleoside coupling with silylated thymine to give all four D-isomers of 3'-azido-3'-deoxythymidine 6-9

Methyl 2,5-dideoxy-5-iodo-3-O-pivaloyl-D-erythro-pentofur-anoside (5) was synthesized from 2-deoxy-D-ribose and treated with triethyl phosphite to give the phosphonate 6. Reaction of 6 with silylated 2,4-dihydroxypyrimidine 7 in the presence of trimethylsilyl trifluoromethanesulfonate as catalyst afforded nucleoside phosphonates 8 and 9 which were deprotected with C2H5ONa in ethanol to give the diethyl 2′,5′-dideoxyuridine-5′-phosphonate 10 and its α-anomer 11. No activity was found for the nucleosides 8–11 against HIV or HSV-1.

We report the first synthesis of the L isomer of 3'-azido-3'-deoxythymidine (L-AZT). L-Arabinose was used as starting material for preparation of appropriately protected α,β-unsaturated aldehyde 5-Michael-type addition of azide to 5 gave 3-azido-2,3-dideoxypentofuranose suitable for nucleoside coupling with silylated thymine to afford after deprotection L-AZT, 1-(3-azido,-2,3-dideoxy-α-L-erythro-pentofuranosyl)thymine, 1-(3-azido-2,3-dideoxy-β-L-threo-pentofuranosyl)thymine and 1-(3-azido-2,3-dideoxy-α-L-threo-pentofuranosyl)thymine. Anti-HIV activity of L-AZT is discussed

1-(3-Alkyl-2,3-dideoxy-alpha,beta-D-erythro-pentofuranosyl)uracils and 1-(3-alkyl-2,3-dideoxy-alpha,beta-D-threo-pentofuranosyl)uracils have been prepared from (E)-4,5-di-O-acetyl-2,3-dideoxy-aldehydo-D-glycero-pent-2-enose by a Michael addition reaction of the appropriate organocopper reagent followed in subsequent order by glycosidation of the resulting 3-alkyl-4,5-diacetoxypentanal with methanolic hydrogen chloride, protection with p-methoxybenzoyl chloride, and trimethylsilyl triflate catalyzed coupling with 2,4-di-O-(trimethylsilyl)uracil. The nucleosides were deprotected by treatment with 33% methylamine in absolute ethanol and separated by reversed-phase HPLC.

The trimethylsilyated 6-dimethylaminopurine 1 was coupled with the 2′,3′-dideoxyribose derivatives 2a, b and 7 by using trimethylsilyl triflate as catalyst to yield the corresponding nucleosides 3a, b, 4a, b and 8, which were appropriately deprotected to give the desired nucleosides 5a, b and 9 as well as the related α-isomers 6a, b and 10. The 2-deoxyribose derivative 12 was mesylated at the 3′-O-position to give 13 which was coupled similarly with 1 to yield compound 14 and its α-anomer 15. Compounds 14 and 15 were treated with tetrabutylammonium fluoride to give the desired 2′,3′-didehydro-2′,3′-dideoxynucleoside analogue 16 and its α-anomer 17.

Reaction of methyl 2-bromo-2,3-dideoxy-5-O-(4-methylbenzoyl)-D-erythro-pentofuranoside (7)with silylated uracils using trimethylsilyl triflate as catalyst afforded the corresponding 2'-bromonucleosides(10). 2,3-Didehydro sugar was prepared by heating 7 with sodium azide in dimethylformamide. 2,2'-Anhydronucleosides were prepared by treating the nucleosides 10 with sodium methoxide at room temperature. 1-(2-Azido-2,3-dideoxy-β-D-threo-pentofuranosyl)thymine (15) and its α-anomer (16) were prepared by treating 10 with sodium azide and subsequently methanolic ammonia

5-Alkoxymethyluracils 2a-c have been prepared by acid-catalyzed etherification of 5-hydroxymethyluracil (1). Compounds 1, 2a-c, 5-methoxymethyl- and 5-benzyloxymethyl-uracil were silylated and coupled with 1,5-di-O-acetyl-3-phthalimido-2,3-dideoxy-beta- D-erythro-pentofuranose (3), in the presence of trimethylsilyl triflate as a catalyst, to give the corresponding 3'-phthalimido-2',3'-dideoxynucleosides 5a-f and 6 which on treatment with 33% methylamine-ethanol afforded the corresponding 3'-amino-2',3'-dideoxynucleosides 7a-f and 8 in high yields. Compound 7d showed colony inhibition when tested against human epidermoid cervical cancer cells. Nucleosides 5a-e, 7a-f and 8 did not show any significant activity against HIV-1.

Mercuric-catalyzed hydrolysis of acetylated L-rhamnal 1 gives an alpha,beta-unsaturated aldehyde 2. 1,4-Addition of DBU-phthalimide salt with concomitant acetyl shift resulted in L-ribo and L-arabino isomers of 5-O-acetyl-2,3,6-trideoxy-3-phthalimido-hexofuranose 3 and 4. After acetylation at the anomeric center, coupling with silylated thymine resulted in three new nucleosides, with L-acosamine and L-ristosamine of furanose configuration as the carbohydrate moiety. The target compounds have been evaluated for their antiviral activity against HIV and HSV-1.

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 α-anomer as the main product. Deprotected nucleosides were obtained by treatment with tetrabutylammonium fluoride.

Condensation of L- and D-3′-amino-2′,3′-dideoxynucleosides 2–5 with N-BOC-protected aminoacids 6 and 13 using dicyclohexylcarbodiimide and N-hydroxysuccinimide in DMF is reported to give the N-BOC-protected acylamino aminonucleosides 7–9 and 14 in 51–81% yield. After deprotection using trifluoroacetic acid the corresponding unprotected new analogues of puromucin 10–12 and 15 were obtained in 43–56% yield. These compounds did not show any significant antiviral activity using HIV (stain HTLV-III B)-infected MT-4 cells as target system.

Acid catalyzed etherification of 5-hydroxymethyluracil (3) afforded the corresponding 5-alkoxymethyluracils (4a-h). Treatment of the sodium salt of compounds (4a-g) with 4-bromobutyl acetate afforded 1,3-bis-(4-acetyloxybutyl)- (5a-g) and 1,4-acetyloxybutyluracil derivetives -6a-g). Alkylation of 4h with 5-chloropentyl benzoate gave 1,3-bis-(5-benzoyloxypentyl)- (8) and 1-(5-benzoyloxypentyl)-5-b-butyloxymethyluracil (9). Ammonolysis of 6a-g and 9 at room temperature gave the corresponding hydroxyalkyl derivatives (7a-g and 10)

The 3'-iodonucleosides 4 have been synthesized by condensation of silylated 5-alkyluracils 2 with methyl 5-O-tert-butyldiphenylsilyl-2,3-dideoxy-3-iodo-D-threo-pentofur anoside (3). 4 was treated with sodium azide and the deprotected nucleoside 5 was subsequently obtained by treatment with tetrabutylammonium fluoride. The nucleoside 4 produced the corresponding 2',3'-didehydro-2',3'-dideoxy nucleoside 6 and 3',4'-didehydro-2',3'-dideoxy nucleoside 7 in elimination reactions on treatment with sodium methoxide.

Direct condensation of 2-deoxy-D-ribose (1) with mercaptans using the P4O10/H2O/Bu3N reagent in chloroform resulted in coupling at C-3 to give the anomeric mixtures of the corresponding pentopyranoses 2 and pentofuranoses 3. After acetylation with acetic anhydride in dry pyridine of these 3-alkylthio pentofuranoses, coupling with the nucleobases uracil, thymine, and cytosine in accordance with the Friedel-Crafts catalyzed silyl Hilbert-Johnson method yielded the acetylated D-erythro nucleosides 7 as anomeric mixtures, separable only by means of chromatography either before or after deprotection with ammonia. The nucleosides 8a-e were devoid of any activity against HSV-1 and HIV-1.

Free-radical reaction of different carbohydrate educts 2, 5, and 7 with acrylonitrile in the presence of tributyltin hydride and a radical initiator (AIBN) gave the methyl 3-(2-cyanoethyl)-2,3-dideoxypentofuranosides 3a and 6. Similar reaction of 2 with methyl acrylate gave 3-(2-methoxycarbonylethyl>-2,3-dideoxypentofuranose 3b. Nucleoside coupling of 3a with silylated uracil gave an anomeric mixture of β- and α-nucleoside 8 and 9 which were deprotected to give 10 and 11, respectively. Similar reaction of 3b with silylated N4-isobutyrylcytosine gave 12 and 13 which were deprotected to give the final nucleosides 16 and 17, respectively. None of the compounds 10a, 11, 14-17 showed significant activity against HIV. Radikalsynthese von 3-(2-Cyanethyl)- und 3-(2-Methoxycarbonylethyl)-2,3-didesoxy-α-D-erythro-pentofuranosid und ihre Anwendung zur Synthese potentiell antiviraler Nucleoside Die Radikalreaktion der Zuckerderivate 2, 5 und 7 mit Acrylnitril in Gegenwart von Tributylzinnhydrid und dem Radikalstaiter AIBN fuhrte zu den Methyl-3-(2-cyanethyl)-2,3-didesoxypentofuranosiden 3a und 6. Die analoge Reaktion von 2 mit Methylacrylat ergab die 3-(2-Methoxycarbonylethyl)-2,3-didesoxypentofuranose 3b. Die Nucleosidverknupfung von 3a mit silyliertem Urazil lieferte das Anomerengernisch der β- und α-Nucleoside 8 und 9, die zu 10 bzw. 11 entsilyliert wurden. Analog dazu wurden aus 3b und silyliertem N4-lsobutyrylcytosin 12 und 13 und durch Entfernen der Schutzgruppen 16 bzw. 17 erhalten. Keine der Verbindungen 10a, 11, 14-17 zeigte nennenswerte Aktivitat gegen HIV.

Methyl 3-azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-D-erythro-furanosi de (3) was coupled with silylated 5-hydroxymethyluracil (1a) and its C1-C6 alkyl ethers 1b-g to give the corresponding protected nucleosides 4a-g which were deprotected with Bu4NF to afford 3-azido nucleosides 5a-g and 6a-g. The alpha-anomers 6f,g show moderate activity against HIV. No significant activity against HSV-1 was found for the compounds 5 and 6.

S-Glycosylation took place on reaction of 5-alkylidene- and 5-arylidene-3-aryl-2-thiohydantoins with glycosyl halides under alkaline conditions. Bisglucosylation also took place when N-3 unsubstituted hydantoins were reacted. The bisglucosylated hydantoins produced N-3 glucosylated hydantoins on treatment with ammonia in methanol. In antiviral studies the most active compounds against both HSV-1 and HSV-2 were 5-(2-thienylmethylene)-3-phenyl-2-(2,3,4,6- tetra-O-acetyl-beta-D-glucopyranosyl)-2-thiohydantoin and 5-(2-thienylmethylene)-3-(4-chlorophenyl)-2-(2,3,4,6-tetra-O-acety l-beta-D- glucopyranosyl)-2-thiohydantoin.

Methyl 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.

Methyl 2,3-dideoxy-3-fluoro-5-0-(4-phenylbenzoyl)-β-D-erythro-pentofuranoside was condensed with trimethylsilylated 5-substituted uracils to give nucleosides using trimethylsilyl trifluoromethanesulfonate as catalyst. In the case of 5-nitrouracil an acyclic nucleoside believed to be an intermediate for the corresponding nucleoside was isolated. The 5-substituents were selected from neural network calculations on compounds with potential activity against HIV-1. All compounds from the condensation reactions were deacylated by treatment with sodium methoxide in methanol

5-Formyl-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)uracil (4) was synthesized from 5-formyluracil (2) and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (3) and condensed with 2-thiohydantoin derivatives 5 by using piperidine as the catalyst to give 5-(uridin-5-ylmethylene)-2-thiohydantoin (8a) and 3-phenyl-5-(uridin-5-ylmethylene)-2-thiohydantoin (8b) after deprotection with sodium methoxide in methanol. Compound 8a was also obtained in an inversed reaction sequence from 5-formyluracil starting with condensation with 2-thiohydantoin and then with 3. The compounds 8a and 8b did not show any activity against HSV-1 or HIV-1.

3′-Azidonucleosides 4 have been synthesized by condensation of silylated (Z)-5-ethylidenehydantoin and (Z)-5-benzylidenehydantoin with methyl 3-azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-D-erythro-pentofuranoside (3). The nucleosides 4 were deblocked on treatment with tetrabutylammonium fluoride. The ethylidene group isomerized from Z to E configuration during the nucleoside synthesis. The new nucleosides did not show any appreciable activities against HIV-1 or HSV-1. Synthese und Prufung auf antivirale Eigenschaften von Hydantoin-Analogen des AZT Die 3′-Azidonukleoside 4 wurden durch Kondensation silylierter (Z)-5-Ethylidenhydantoine und (Z)-5-Benzylidenhydantoine mit Methyl-3-azido-5-O-tert-butyldiphenylsilyl-2,3-didesoxy-D-erythro-pentofuranosid (3) hergestellt. Die Schutzgruppen der Verbindungen 4 wurden mit Tetrabutylammoniumfluorid entfernt. Die Ethylidengruppe isomerisierte von der Z- in die E-Konfiguration wahrend der Nukleosid-Synthese. - Die neuen Verbindungen zeigen keine nennenswerten Wirkungen gegen HIV-1 und HSV-1.

Alkylation of 5′-O-tritylthymidine with dialkylaminoalkyl chlorides in the presence of sodium hydride yields 3′-O-dialkylaminoalkyl-5′-O-tritylthymidine derivatives2 which were treated with an excess of iodomethane to afford the corresponding quaternary ammonium derivatives3. Deprotected nucleosides4 and6 were obtained by refluxing3 and2, respectively, in 80% acetic acid. When the compounds2–4 and6 were investigated for activity against HSV and HIV, the trityl derivatives2a and2c were found active against HSV.

1-(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.

Silylated 4-methylthiouracil and 4-methylthiothymine were condensed in the presence of TMS triflate with methyl 2,3-dideoxy-3-fluoro-5-O-(4-phenylbenzoyl)-D-erythro-pentofuranoside (3) and methyl 3-azido-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-D-erythro-pentofuroside (8), respectively, to give the corresponding nucleosides which were deprotected. The 3′-azido nucleoside was reduced with triphenylphosphine to the corresponding 3′-amino nucleoside. The 3′-amino nucleoside was also obtained by condensation of 4-methylthiothymidine with a 3-phthalimido sugar 14 followed by deprotection. The 4-methylthio analogue 11 of AZT showed moderate activity against HIV. Synthese von 4-Methylthioanalogen des FLT und AZT und ihre Prufung auf Anti-HIV-Wirkung Silyliertes 4-Methylthiouracil und 4-Methylthiothymin wurden in Gegenwart von TMS-Triflat mit Methyl-2,3-didesoxy-3-fluoro-5-O-(4-phenylbenzoyl)-D-erythro-pentofuranosid (3) und Methyl-3-azido-5-O-(tert-butyldiphenylsilyl)-2,3-didesoxy-D-erythro-pentofuranosid (8) zu den entspr. Nukleosiden kondensiert. Anschliesend wurden die Schutzgruppen entfernt. Das 3-Azidonukleosid wurde mit Triphenylphosphin zum entspr. 3-Aminonukleosid reduziert, das auch durch Kondensation von 4-Methylthiothymidin mit dem 3-Phthalimido-Zucker 14 und Abspaltung der Schutzgruppen erhalten wurde. - Das 4-Methylthio-Analogen 11 des AZT ist gegen HIV schwach wirksam.

Reaction of methyl 2-deoxy-5-O-(4-phenylbenzoyl)-β-D-erythro-pentofuranoside 2 with diethylaminosulfur trifluoride (DAST) in a 1:10 molar ratio in CH 2 Cl 2 at room temperature for 5 d afforded methyl 2,3-dideoxy-3-fluoro-5-O-(4-phenylbenzoyl)-β-D-erythro-pentofuranoside 4 in 57% yield, while the α-anomer 9 under the same reaction conditions yielded the 3-fluoro-α-D-erythro derivative 10 in 14% yield together with the 5-fluoro-α-D-threo derivative 11 in 22% yield. (Z)-5-Benzylidene-, (E)-ethylidene- and 5,5-dimethylhydantoin nucleosides were obtained by condensation of the appropriate silylated nucleobases with 4 The protected nucleosides were in all cases deblocked by treatment with sodium methoxide in methanol. The (Z)-ethylidene group isomerized to the E configuration during the nucleoside synthesis