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 Alkylating 1-Glycosyl-5-substituted 1,2,4-Triazoles1

Abstract

A series of alkylating derivatives of 5-subs-tituted 1-glycosyl-1,2,4-triazole having cytostatic activity has been prepared. The compounds synthesized include the 5-hydroxymethyl, 5-halomethyl, 5-(1-aziridino) methyl, and 5-bis (2-chloroethyl) aminomethyl derivatives.     

STEREOSELECTIVE SYNTHESIS OF 3-HYDROXYMETHYL-D-CYCLOPENTENONE,THE VERSATILE INTERMEDIATE FOR THE SYNTHESIS OF CARBOCYCLIC NUCLEOSIDES

The preparative and stereoselective synthesis (45–50% overall yields, >50 g scale) of the key carbasugars 7a–d was achieved from D-ribose via stereoselective Grignard reaction and oxidative rearrangement as key reactions.     

Open-Chain Carbocyclic Analogs of Adenosine with Dihalovinyl Unit as Potential Inhibitors of S-Adenosyl-L-homocysteine Hydrolase

Abstract

Vinylogously extended deoxyeritadenine derivatives were synthesized as acyclic/carbocyclic analogues of the 6′-halo(homovinyl)adenosines, which are known to be potent inhibitors of S-adenosyl-L-homocysteine hydrolase. Swern oxidation of 9-[3-(t-butyldimethylsilyloxy)-4-hydroxybutyl]adenine (4) followed by Wittig olefination and desilylation gave access to ethyl 6-(adenin-9-yl)-4-hydroxy-2(E)-hexenoate (7) and 5-(adenin-9-yl)-1,1-dibromo-1-penten-3-ol (9). No inhibition of AdoHcy Hydrolase was observed with 7 and 9.     

Synthesis of Carbocyclic Analogues of MECA and NECA 1,2-Disubstituted as Potential Adenosine Receptor Agonists

Abstract

A new class of 1,2-disubstituted carbocyclic nucleosides of MECA and NECA analogues was synthesized in gool yield starting from (±) 6-azabicyclo[3.2.0]heptan-7-one.     

Synthesis and Conformational Analysis of a Locked Analogue of Carbovir Built on a Bicyclo[3.1.0]-hex-2-enyl Template

Abstract

The synthesis and biological evaluation of a carbovir analogue (5) built on a bicyclo[3.1.0]hex-2-enyl template is described. A conformational analysis using density functional theory at the B3LYP/6-31G* level has been carried out on the rigid pseudosugar template of 5, the cyclopentene moiety of carbovir and the bicyclo[3.1.0]hex-2-yl pseudosugars of two isomeric carbonucleosides (12 and 13) containing exo- and endo-fused cyclopropane rings. The results show that while the planar configuration of the fused cyclopentane ring of compound 5 helps retain weak anti-HIV activity, the ability of the cyclopentene ring of carbovir to easily adopt a planar or puckered conformation with little energy penalty may prove to be a crucial advantage. The bicyclo[3.1.0]hex-2-yl nucleosides 12 and 13 that were inactive against HIV exhibited stiffer resistance to having a planar, fused cyclopentane moiety.     

Efficient Synthesis of 4′-Cyclopropylated Carbovir Analogues with Use of Ring-Closing Metathesis from Glycolate

The first synthetic route of novel 4′-cyclopropylated carbovir analgues is described. The construction of cyclopropylated quaternary carbon at 4′-position of carbocyclic nucleosides was successfully made via sequential Johnson's orthoester rearrangement and ring-closing metathesis (RCM) starting from ethyl glycolate. Synthesized compounds 15 and 16 showed moderate antiviral activity without any cytotoxicity up to 100 μmol.     

Synthesis of Cyclobutane Nucleosides

2-(6-Chloropurinyl)-3-benzoyloxymethylcyclobutanone can be prepared by reaction of 6-chloropurine with 3-benzoyloxymethyl-2-bromocyclobutanone. The N-alkylation gave both N-9 and N-7 regioisomers. Both regioisomers upon hydride reduction followed by aminolysis gave the corresponding adenine nucleoside analogues. However, the N-7 series led to the hypoxanthine analogues as byproducts.     

6′-Methyl-5′-homoaristeromycin: A structural variation of the anti-orthopox virus candidate 5′-homoaristeromycin

The synthesis of 6′-methyl-5′-homoaristeromycin is described from a known 6′-ethyl ester. Antiviral analysis showed the (S)-6′ stereoisomer retained the vaccinia activity of the parent 5′-homoaristeromycin (1) while the (R)-6′ isomer was less active. Both were weaker than 1 towards cowpox. The diastereomers were equally active versus Epstein Barr virus while (S)-6′ was three times more active toward vesicular stomatitis virus than (R)-6′. The diastereomers were inactive towards numerous other viruses. The CC₅₀ for both diastereomers was >300 μM.     

Synthesis,characterization and preliminary screening of regioisomeric 1-(3-pyridazinyl)-3-arylpyrazole and 1-(3-pyridazinyl)-5-arylpyrazole derivatives towards cyclooxygenase inhibition

In a search for novel compounds with analgesic and anti-inflammatory activity, a series of regioisomeric 1-(3-pyridazinyl)-3-arylpyrazole (5a–f, 6a–f) and 1-(3-pyridazinyl)-5-arylpyrazole (7a–f, 8a–f) derivatives were synthesized. The structure of these regioisomers was confirmed by spectral techniques. The compounds were preliminarily screened at 8 μM concentration for their inhibitory activity against cyclooxygenase enzymes, COX-1 and COX-2, using a human whole blood test. The tested derivatives showed inhibitory activity for both enzymes and are worthy of further investigation for developing better leads.     

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).     

SYNTHESIS AND BIOLOGICAL ACTIVITY OF 4-SUBSTITUTED 1-[1-(2-HYDROXYETHOXY)- METHYL-1,2,3-TRIAZOL-(4 & 5)-YLMETHYL]-1H-PYRAZOLO[3,4-d]PYRIMIDINES

The chemical synthesis of some 4-substituted 1-[1-(2-hydroxyethoxy)methyl-1,2,3-triazol-(4 and 5)-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidines 12a,b, 13a,b and 14–23 as acyclic nucleosides is described. Treatment of (2-acetoxyethoxy)methylbromide with sodium azide afforded (2-acetoxyethoxy)methylazide 9. The heterocycles 6a,b were alkylated, separately, with propargyl bromide to obtain, regioselectively, 4-(methyl and benzyl)thio-1-(prop-2-ynyl)-1H-pyrazolo[3,4-d]pyrimidines 7a,b. These N₁-alkylated products were condensed with compound 9 via a 1,3-dipolar cycloaddition reaction to obtain, after separation and deprotection, 1,4 and 1,5-regioisomers 12a,b and 13a,b. The deprotected acyclic nucleosides 12a and 13a served as precursors for the preparation of 4-amino (14 and 15), 4-methylamino (16 and 17), 4-benzylamino (18 and 19), 4-methoxy (20 and 21) and 4-hydroxy (22 and 23) analogues. Compounds 7a,b and all deprotected acyclic nucleosides were evaluated for their inhibitory effects against the replication of HIV-1(III_B) and HIV-2(ROD) in MT-4 cells and for their anti-tumor activity. No marked activity was found. However, initial evaluation of 6a,b, 7a,b, 12a,b, 13a,b and 14–23 showed that compound 7b has marked activity against M. tuberculosis.     

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 and Anti-HCV Activity of 4-Methoxy-7H-Pyrrolo[2,3-d] Pyrimidine Carbocyclic Nucleosides

The present study includes the exploration of new possible nucleoside mimetics based on 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine carbocyclic nucleosides (4a–g), which were synthesized by 10–15 synthetic steps and characterized adequately. We report the anti-HCV activities and cytotoxicities of 4a–g. Compound 4a was analyzed by single crystal X-ray diffraction which showed some puckering in the cyclopentene ring with a 2′-endo conformation and anti-base disposition (χ = ?125.7°).     

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.     

First Synthesis and Anti-HIV Evaluation of 4′-Methyl-Cyclopentanyl 9-Deazaadenosine

The first synthesis of a 4′-methylated carbocyclic C-nucleoside 16 was achieved via the mesylate intermediate 10, which was prepared using ring-closing metathesis and S_N2 alkylation from acetol 5. When antiviral evaluation of synthesized compound 16 was performed against various viruses such as HIV, HSV-1, HSV-2, and HCMV, it showed moderate anti-HIV activity in MT-4 cell line (EC₅₀ = 14.7 μmol).     

Ligand design,synthesis and biological anti-HCV evaluations for genotypes 1b and 4a of certain 4-(3- & 4-[3-(3,5-dibromo-4-hydroxyphenyl)-propylamino]phenyl) butyric acids and 3-(3,5-dibromo-4-hydroxyphenyl)-propylamino-acetamidobenzoic acid esters

4-(4-[N-1-carboxy-3-(3,5-dibromo-4-hydroxyphenyl)-3-oxo-propylamino]phenyl)-4-oxo-butyric acid (V), 4-(3- & 4-[N-1-carboxy-3-(3,5-dibromo-4-hydroxyphenyl)-3-oxo-propylaminophenyl]-2-aryl-4-oxo-butyric acids (Xa–e) and 4-(2-alkyl-2-[N-3-(3,5-dibromo-4-hydroxyphenyl)-1-carboxy-3-oxo-propylamino]acetamido) benzoate esters (XVa–e) were designed, synthesized and biologically evaluated as anti-HCV for genotypes 1b and 4a. The design was based on their docking scores with HCV NS3/4A protease-binding site of the genotype 1b (1W3C), which is conserved in the genotype 4a structure. The docking scores predicted that most of these molecules have higher affinity to the HCV NS3/4A enzyme more than Indoline lead. These compounds were synthesized and evaluated for their cytopathic inhibitory activity against RAW HCV cell cultures of genotype 4a and also examined against Huh 5–2 HCV cell culture of genotype 1b, utilizing Luciferase and MTS assays. Compounds Xa and Xb have 95 and 80% of the activity of Ribavirin against genotype 4a and compounds XVa, XVb and XVd exerted high percentage inhibitory activity against genotype 1b equal 87.7, 84.3 and 82.8%, respectively, with low EC₅₀ doses.     

Synthesis,conformational study and antiviral activity of l-like neplanocin derivatives

The l-like enantiomer of 9-(trans-2′, trans-3′-dihydroxycyclopent-4′-enyl)-3-deazaadenine (DHCDA) (1), its 3-deaza-3-bromo derivative (3), and the conformational restricted methanocarba (MC) nucleoside analogues (2 and 4) were synthesized. X-ray crystal structures showed the L isomer MC analogue 4 adopts a similar North-like locked conformation as conventional D-MC nucleosides, while the DHCDA analogue 3 preferred south-like conformer. Compounds 1 and 4 showed potent antiviral activity against norovirus, while compound 2 and 3 were less potent or inactive. The conformational behavior of “sugar” puckering (north/south) and nucleobase orientation (syn /anti) may contribute to the antiviral activity differences. For compound 3, antiviral activity was also found against Ebola virus.     

Microbial synthesis of S (+)-1-(2-furyl)-3-pentanol: A pheromone intermediate of bark beetle

Summary The synthesis of S (+)-1-(2-furyl)-3-pentanol (3), a key intermediate in the synthesis of chalcogran (1) is described via microbial reduction of 1-(2-furyl)-1-pentene-3-one (2) using fungusRhizopus arrhizus.     

SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME 4-SUBSTITUTED 1-[1-(4-HYDROXYBUTYL)-1,2,3-TRIAZOL-(4 & 5)-YLMETHYL]-1H-PYRAZOLO-[3,4-d]PYRIMIDINES

The synthesis of 1-[1-(4-hydroxybutyl)-1,2,3-triazol-(4 and 5)-ylmethyl] -1H-pyrazolo[3,4-d]pyrimidines 11a,b, 12a,b and 13–17 as carboacyclic nucleosides is described. The compounds 8a,b were condensed, separately, with compound 7 via 1,3-dipolar cycloaddition reaction to afford, after separation and deprotection, 1,4-regioisomers 11a,b and 1,5-regioisomers 12a,b. The deprotected carboacyclic nucleosides 11a served as precursor for the preparation of 4-amino 13, 4-methylamino 14, 4-benzylamino 15, 4-methoxy 16 and 4-hydroxy 17 analogues. All deprotected carboacyclic nucleosides were evaluated for their inhibitory effects against the replication of HIV-1(III_B), HIV-2(ROD), various DNA viruses, a variety of tumor-cell lines and tuberculosis. No marked biological activity was found.