Synthesis of (±)-4′-Ethynyl and 4′-Cyano Carbocyclic Analogues of Stavudine (d4T)

The synthesis of (±)-4′-ethynyl (8) and 4′-cyano (9) carbocyclic analogues of the anti-HIV agent stavudine (5, d4T) is reported. The carbocyclic unit (16) was constructed from readily available β-keto ester 10. The ethynyl or cyano group of 8 and 9 were prepared, after the introduction of thymine base to 16, by manipulation of the ester function. Evaluation of the anti-HIV activity of 8 and 9 was also carried out.     

Synthesis of Novel 3′-Hydroxymethyl 5′-Deoxythreosyl Phosphonic Acid Nucleoside Analogues as Potent Antiviral Agents

A very efficient synthetic route to novel 3′-hydroxymethyl 5′-deoxythreosyl phosphonic acid nucleosides was described. The discovery of threosyl phosphonate nucleoside (PMDTA, EC₅₀ = 2.53 μM) as a potent antihuman immunodeficiency virus (anti-HIV) agent has led to the synthesis and biological evaluation of 3′-modified 5′-deoxy versions of the threosyl phosphonate nucleosides. 3′-Hydroxymethyl 5 ′-deoxythreosyl phosphonic acid nucleoside analogues 15, 19, 24, and 28 were synthesized from 1,3-dihydroxyacetone and tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 19 exhibits moderate in vitro anti-HIV-1 activity (EC₅₀ = 10.2 μM).     

Novel Carbocyclic Nucleosides Containing A Cyclobutyl Ring. Guanosine and Adenosine Analogues

Abstract

(1R,cis)-2-(3-Amino-2,2-dimethylcyclobutyl)ethanol (4) was used as a precursor in the synthesis of cyclobutyl nucleoside analogues containing guanine, 8-azaguanine, adenine or 8-azaadenine. All the compounds were evaluated as antiviral agents in a variety of assay systems. Some activity was noted for compound 13, 17, 19 and 20 against vaccinia virus and for compounds 11, 12, 13, 17, 19 and 20 against herpes simplex virus, at concentrations that were up to 10-fold below the cytotoxic concentrations for the host cells.     

Synthesis and Biological Activities of Sugar-Modified 2-(p-n-Butylanilino)-2′-deoxyadenosine Analogues

Abstract

Several sugar-modified 2-(p-n-butylanilino)-2′-deoxyadenosine analogues, including arabino and 2′(R)-azido-2′-deoxy analogues and their 5′-triphosphates were synthesized. These nucleosides thus obtained exhibited moderate cytotoxicity against P-388 leukemic cells in culture (IC₅₀ = 13–24 μ). In contrast to above results, the 5′-triphosphates have been shown to exert strong and selective inhibitory effects on mammalian DNA polymerase α (Ki= 0.02–0.04 μ).     

Synthesis and Biological Application of a New Heterodinucleotide with Both Anti-HSV and Anti-HIV Activity

Abstract

A new antiviral drug with both anti-HSV and anti-HIV activity was synthesized by coupling Acyclovir and the acyclic nucleoside phosphonate (R)PMPA. The heterodinucleotide ACVpPMPA encapsulated into autologous erythrocytes was added to human macrophages providing an effective in vitro protection from HSV-1 and HIV-1 replication.     

Asymmetric Synthesis and Biological Activity of l-Bicyclocarba-d4T

Novel l-bicyclocarba-d4T (1), an enantiomer of d-N-MCd4T has been enantiopurely synthesized as a potent anti-HIV agent starting from (R)-epichlorohydrin using tandem alkylation, chemoselective reduction of ester in the presence of lactone functional group, Grignard reaction, RCM reaction, and Mitsunobu reaction as key steps. l-N-MCd4T (1) was found to be very potent anti-HIV-1 (EC₅₀ = 6.76 μg/mL) agent with no cytotoxicity.     

Antiviral Nucleoside Analogues with Axial Chirality

Abstract

Chemistry and biological activity of nucleoside analogues comprising a chiral axis will be reviewed with emphasis on anti-HIV agent adenallene (1a) and anti-HIV/HBV analogue cytallene (1b). Possible mechanism of action, activity toward the enzymes of nucleic acid metabolism and structure-activity relationships will be discussed.     

Asymmetric Hydrolysis of (R,S)-5-Acetoxymethyl-3-tert-butyl-oxazolidin-2-one with Enzymes and Microorganisms†

Enzymes and microorganisms were screened for the asymmetric hydrolysis of (R, S)-5-acetoxymethyl-3-tert-butyl-oxazolidin-2-one 1. Lipases from Pseudomonas aeruginosa and Alcaligenes species, and microorganisms which belong to Enterobacter species or Klebsiella species were found to hydrolyze 1 enantioselectively to give (R)-5-hydroxymethyl-3-tert-butyl-oxazolidin-2-one (R)-2 and (S)-l. (S)-2, one of the typical intermediates for preparing optically active β-blocking agents (β-blockers), was obtained with high enantiomeric excess (91~98% e.e.) from (S)-1.     

Anti-HIV Derivatives of 1-(2,3-Dideoxy-3-N-hydroxyamino-β-D-threo-pentofuranosyl)thymine

Abstract

Representative examples of the title compounds including bicyclic analogs (7–9) in which a perhydro-1,3-oxazine is ortho-fused to the furanose ring, have been prepared in good to excellent yields. Compounds 5 and 7 showed marked activity against HIV-1 and HIV-2 replication in CEM cells (50% inhibitory concentration: 0.80–4.3μg/mL). Their di-O-acetylated (6) and mono-O-acetylated (8) derivatives were considerably less effective. To the best of our knowledge, these β-D-threo anti-HIV nucleoside analogs constitute the first examples of anti-HIV active nucleosides bearing this configuration.     

Synthesis and Biological Evaluation of 1,3-Oxathiolane 5-Azapyrimidine, 6-Azapyrimidine,and Fluorosubstituted 3-Deazapyrimidine Nucleosides

Abstract

(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19–24) have been synthesized by the transglycosylation of (2R,5S)-1-{2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-y1} cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B₁₆F₁₀, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.     

Synthesis of Novel 2′,3′-Difluorinated 5′-Deoxythreosyl Phosphonic Acid Nucleosides as Antiviral Agents

A novel route for the synthesis of 2′,3′-difluorinated 5′-deoxythreosyl phosphonic acid nucleosides from glyceraldehyde using the Horner-Emmons reaction in the presence of triethyl α-fluorophosphonoacetate is described. The second fluorination at the 2′-position was an electrophilic reaction performed using N-fluorodibenzenesulfonimide. Glycosylation reactions between the nucleosidic bases and glycosyl donor 9 generated nucleosides that were further phosphonated and hydrolyzed to produce the desired nucleoside analogues. The synthesized nucleoside analogues 13, 16, 20, and 23 were tested for anti- human immunodeficiency virus (HIV) activity as well as cytotoxicity. Adenine derivative 16 showed significant anti-HIV activity up to 100 μM.     

Synthesis of Novel 2′-Fluoro-3′-Hydroxymethyl-5′-Deoxythreosyl Phosphonic Acid Nucleoside Analogues As Antiviral Agents

A series of purine 5′-deoxyphosphonate analogues were designed and synthesized to mimic naturally occurring purine monophosphate from 1,3-dihydroxyacetone as starting material. The discovery of threosyl phosphonate nucleoside (PMDTA, EC₅₀ = 2.53 μM) as a potent anti-HIV agent has led to the synthesis and biological evaluation of 2′,3′-modified 5′-deoxyversions of the threosyl phosphonate nucleosides. The synthesized 2′-fluoro-3′-hydroxymethyl 5′-deoxythreosyl phosphonic acid nucleoside analogues 14, 18, 23, and 27 were tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 18 exhibits weak in vitro anti-HIV-1 activity (EC₅₀ = 19.2 μM).     

Methylenecyclopropane Analogues of Nucleosides: Synthesis,Absolute Configuration,and Enantioselectivity of Antiviral Effect of (R)-(-)- and (S)-(+)-Synadenol

Abstract

Synthesis, absolute configuration and antiviral activity of enantiomeric antiviral agents (R)-(-)- and (S)-(+)-synadenol (2 and 3a) are described.     

Asymmetric Hydrolysis of Prochiral Diesters with Pig Liver Esterase. Preparation of Optically Active Intermediates for the Synthesis of (+)-Biotin and (+)-α-Methyl-3,4-dihydroxyphenylalanine

With pig liver esterase, 1,3-dibenzyl-4,5-cis-bis(alkyloxycarbonyl)-2-oxoimidazolidine (1) was asymmetrically hydrolyzed to (4S,5R)-1,3-dibenzyl-5-alkyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (2). This acid 2 was reduced with lithium borohydride to (4S,5R)-1,3-dibenzyl-5-hydroxymethyl-2-oxoimidazolidine-4-carboxylic acid lactone (3), which is known to be converted to (+)-biotin (4). With the same esterase, diethyl 3,4-dimethoxyphenylmethyl-(methyl)malonate (5) was asymmetrically hydrolyzed to (R)-ethyl hydrogen 3,4-dimethoxy-phenylmethyl(methyl)malonate (6), which can be converted to (S)-α-methyl-3,4-dihydroxyphenyl-alanine(l-α-methyldopa) (9).     

Synthesis of Novel 4′-Cyclopropyl-5′-norcarbocyclic Adenosine Phosphonic Acid Analogues

Novel 4′-cyclopropyl-5′-norcarbocyclic adenosine phosphonic acid analogues were designed and racemically synthesized from propionaldehyde 5 through a de novo acyclic stereoselective route using triple Grignard addition and ring-closing metathesis (RCM) as key reactions. To improve cellular permeability and enhance the anti-HIV activity of this phosphonic acid, SATE phosphonodiester nucleoside prodrug 23 was prepared. The synthesized adenosine phosphonic acids analogues 17, 18, 19, 21, and 23 were subjected to antiviral screening against HIV-1. Compound 23 exhibits enhanced anti-HIV activity than its parent nucleoside phosphonic acid 18.     

Synthesis and Fluorescent Properties of 6-(4-Biphenylyl)-3,9-dihydro-9-oxo-5H-imidazo[1,2-A]purine Analogues of Acyclovir and Ganciclovir

Abstract

Tricyclic (T) analogues of acyclovir (ACV, 1) and ganciclovir (GCV, 2) carrying the 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine system [i.e., 6-(4-BrPh)TACV, 5 and 6-(4-BrPh)TGCV, 6] were transformed into 6-[(4′-R²)-4-biphenylyl] derivatives of TACV (7–9) and TGCV (10–12) by Suzuki cross coupling with 4-substituted phenylboronic acids. Compound 11 (R² = CH₂OH) showed a high (～1000) selectivity index against herpes simplex virus type 1 (HSV-1) together with advantageous fluorescence properties (emission in visible region, little overlap with absorption and moderate intensity).     

Synthesis and Evaluation of Anti-HIV-1 and Antitumor Activity of 2′,3′-didehydro-2′,3′-dideoxy-3-deazaadenosine, 2′,3′-dideoxy-3-Deazaadenosine and Some 2′,3′-dideoxy-3-deaza-adenosine 5′-dialkyl Phosphates1

Abstract

- The 4-amino-1-(2.3-dideoxy-β-D-glycero-pent-2-enofurano-syl)-1H-irnidazo[4,5-c]pyridine (1) and 4-amino-1-(2,3-dideoxy-β-D-gfycero-pentofuranosyl)-1H-imidazo[4,5-c]pyridine (2), 3-deaza analogues of the anti-HIV agents 2′.3′-didehydro-2′,3′-dideoxyadenosine (d4A) and 2′,3′-dideoxy-adenosine (ddA), have been synthesized. The reaction of 3-deazaadenosine (3) with 2-acetoxyisobutyryl bromide yielded a mixture of cis and trans 2′,3′-ha-lo acetates which was convertcd into olefinic nucleoside (1) on treatment with a Zn/Cu couplc and then with methanolic ammonia. The 2′,3′-dideoxy-3-deazaadenosine (2) was obtained by catalytic reduction of 1. A number of phosphate triester derivatives of 2 have also been prepared. The diethyl-, dipropyl- and dibutylpliospliates 7a-c and 3-deazaadenosine have shown anti-HIV activity at non-cytotoxic doses. Compounds 7a-c have also shown significant cytostatic activity against murine colon adenocarcinoma cells.     

Effects of Trialkyltin Chlorides on Escherichia coli Spheroplasts

Valsa ceratosperma, which is the pathogenic fungus of apple canker, was grown in a synthetic medium. The neutral extract from the culture filtrate was chromatographed on a silica gel column to give five isocoumarins. Their structures were determined by MS, UV, IR, ¹H and ¹³C NMR, and CD spectra. Three of them were known compounds; ( ? )-5-methylmellein (1), ( ? )-5-carboxylmellein (2) and ( ? )-5-hydroxylmethylmellein (3). Since the absolute configurations at C-3 in 2 and 3 were not known until now, both were determined to be R by chemical correlations. The two were new compounds; ( + )-(3R,4S)-trans-4-hydroxy-5-methylmellein (4) and ( ? )-(3R,4R)-cis-4-hydroxy-5-methylmellein (5). All the five compounds showed phytotoxicity in a bioassay using detached apple shoots and lettuce seedlings.     

Efficient Synthesis of (22R,23R,24S)-22,23-Isopropylidenedioxy-5α-ergost-2-en-6-one,a Key Intermediate in the Preparation of Brassinolide

(22R,23R,24S)-22,23-Isopropylidenedioxy-5α-ergost-2-en-6-one 2b is an important intermediate of brassinolide. We found that the enone 2b can be prepared by transformation of (22R,23R,24S)-3α,5-cyclo-22,23-isopropylidenedioxy-5α-ergostan-6-one 5b with catalytic amount of both p-TsOH and NaBr in DMF under reflux. 5b was prepared from (22R,23R,24S)-3α,5-cyclo-22,23-dihydroxy-6β-methoxy-5α-ergostane 9b or a 6β-benzyloxy compound 9c, which was obtained in a manner similar to Mori’s brassinolide synthesis. The enone 2b was eventually prepared via a benzyl ether 9c from stigmasterol 3a in a 15.5% yield in 11 steps.