Larvicidal isoxazoles: Synthesis and their effective susceptibility towards Aedes aegypti larvae

Twenty 3,5-disubstituted isoxazoles have been synthesized and tested against fourth instar Aedes aegypti larvae. In the synthesis of title compounds, modifications have been made in the C-5 side-chain with a view to test their larvicidal activity. These isoxazoles have been obtained by 1,3-dipolar cycloaddition of arylnitrile oxides to terminal alkynes which furnished the desired products in 20% to 79% yields. A comparative study of the larvicidal activity between 3-(3-aryl-isoxazol-5-yl)-propan-1-ols and 3-(3-aryl-isoxazol-5-yl)-propionic acids clearly demonstrated that the latter compounds possess much better larvicidal activity than the former. We also tested two esters, viz., methyl 3-[3-(phenyl)-isoxazole-5-yl] propionate and methyl 3-[3-(4-chlorophenyl)-isoxazole-5-yl] propionate, where the latter presented an excellent larvicidal profile.     

Synthesis and biological evaluation of phosphonated dihydroisoxazole nucleosides

Phosphonated isoxazolinyl nucleosides have been prepared via 1,3-dipolar cycloaddition reaction of nitrile oxides with corresponding vinyl or allyl nucleobases for antiviral studies. The cytotoxicity, the anti-HSV activity and the RT-inhibitory activity of the obtained compounds were evaluated and compared with those of AZT and diethyl{(1'SR,4'RS)-1'-[[(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)]-3'-methyl-2'-oxa-3'-azacyclopent-4'-yl]}methylphosphonate, a saturated phosphonated dihydroisoxazole nucleoside analogue.     

The Synthesis of Carbocyclic 5′-Nor Thymidine and an Isomer as Oligonucleotide Monomers

Abstract

The chiral synthesis of (1S,3S,4S)-1-(3,4-dihydroxycyclopent-1-yl)-1H?thymine (carbocyclic 5′-nor thymidine, 4) has been achieved in 5 steps from (+)-(lR,4S)-4-hydroxy-2-cyclopenten-1-yl acetate (5) and N³?benzoylthymine. Compound 4 is viewed as a monomeric building block for poly-T-like oligomers.     

Synthesis of 1-(3-Azido-2,3-Dideoxy-Beta-D-Ribo-Hexofuranosyl)Thymine

Abstract

The nucleoside derivative 1-(3-azido-2,3-dideoxy-beta-D-ribo-hexofuranosyl)thymine has been synthesized from 3-0-benzyl-1,2-0-isopropylidene-alpha-D-glucofuranose-5,6-carbonate in an overall yield of 16%. The key step in the synthesis involves the selective deacetylation of a nucleoside derivative having a cyclic carbonate moiety.     

High-yielding cascade enzymatic synthesis of 5-methyluridine using a novel combination of nucleoside phosphorylases

Abstract

A novel combination of Bacillus halodurans purine nucleoside phosphorylase (BhPNP1) and Escherichia coli uridine phosphorylase (EcUP) has been applied to a dual-enzyme, sequential, biocatalytic one-pot synthesis of 5-methyluridine from guanosine and thymine. A 5-methyluridine yield of >79% on guanosine was achieved in a reaction slurry at a 53 mM (1.5% w/w) guanosine concentration. 5-Methyluridine is an intermediate in synthetic routes to thymidine and the antiretroviral drugs zidovudine and stavudine.     

Nucleoside Analogues on the Basis of 4(R),5(R)-Dihydroxymethyl-2-methyl-1,3-dioxolane

Abstract

New nucleoside analogues on the basis of 4(R), 5(R)-dihydroxymethy1-2-methyl-1,3-dioxoiane have been prepared. Alkylation of thymine, adenine and N² -palmitoyl-guanine with 2-bromomethyl-4(R),5(R)-dibenzyloxymethyl-1,3-dioxolane followed by separation of regio isomers by adsorption chromatography and deprotection yielded the desired chiral nucleoside analogues. The structures of thus prepared compounds were confirmed by UV and PMR spectroscopy. The obtained compounds 11 have no anti-HIV and ant i herpetic activity and are not cytotoxic.     

Properties of Oligonucleotide with Phenyl-Substituted Carbocyclic Nucleoside Analogs for the Formation of Duplex and Triplex DNA

(1S,3S,4R)-1-Phenyl-1-thymidyl-3-hydroxy-4-hydroxymethylcyclopentane (10) and their analogs were synthesized, incorporated into the oligodeoxynucleotides, and their properties were evaluated for the formation of duplex and triplex DNA. The known chiral cyclopentanone derivative was converted into the corresponding ketimine sulfonamide derivative, which was subjected to a stereoselective PhLi addition. The formed sulfonamide was hydrolyzed to afford the primary amino group, on which the thymine moiety was built. The benzyl protecting groups were removed to form the nucleoside analog having a phenyl group and the thymine unit at the 1′ position of a carbocyclic skeleton (10). In the estimation of the oligodeoxynucleotides incorporating 10 for duplex and triplex formation, the carbocyclic nucleoside analog 10 did not show the stabilizing effect for duplex formation; on the other hand, it stabilized the triplex. Therefore, the skeleton of the phenyl-substituted carbocyclic nucleoside analog 10 may be a platform for the formation of stable triplex DNA.     

Design and Synthesis of Triazole-Linked xylo-Nucleoside Dimers

Three triazole-linked nonionic xylo-nucleoside dimers T^L-t-T^xL, T^L-t-A^BzxL and T^L-t-C^BzxL have been synthesized for the first time by Cu(I) catalyzed azide-alkyne [3 + 2] cycloaddition reaction (CuAAC) of 1-(3′-azido-3′-deoxy-2′-O,4′-C-methylene-β-D-ribo-furanosyl)thymine with different alkynes, i.e., 1-(5′-deoxy-5′-C-ethynyl-2′-O,4′-C-methylene-β-D-xylofuranosyl)thymine, 9-(5′-deoxy-5′-C-ethynyl-2′-O,4′-C-methylene-β-D-xylo-furanosyl)-N6-benzoyladenine and 1-(5′-deoxy-5′-C-ethynyl-2′-O,4′-C-methylene-β-D-xylofuranosyl)-N4-benzoylcytosine in 90%–92% yields. Among the two Cu(I) reagents, CuSO₄.5H₂O-sodium ascorbate in THF:^tBuOH:H₂O (1:1:1) and CuBr.SMe₂ in THF used for cycloaddition (click) reaction, the former one was found to be better yielding than the latter one.     

Lipase Catalyzed Diastereoselective Deacetylations of Anomeric Mixtures of Peracetylated 2′-Deoxynucleosides

Abstract

Lipase catalyzed deacetylations of anomeric mixtures of peracetylated 2′-deoxyribofuranosyl- and 2′-deoxyribopyranosyl thymine nucleosides 1 and 5 have been investigated. Generally, the diastereoselectivity was more pronounced in pure phosphate buffer than in phosphate buffer containing 10% DMF. Wheat Germ Lipase and Porcine Liver Esterase catalyzed diastereoselective deacetylation of 1 affording the pure β-anomer thymidine (4β) as the only completely deprotected nucleoside product.     

Thiosugar Nucleosides. Synthesis and Biological Activity of 1,3,4‐Thiadiazole,Thiazoline and Thiourea Derivatives of 5‐Thio‐d‐Glucose

New acylated 5‐thio‐β‐d‐glucopyranosylimino‐disusbstituted 1,3,4‐thiadiazols 8, and 11 were prepared, via spontaneous rearrangements, by cycloaddition of the glycosyl isothiocyanate 2 with the reactive intermediates 1‐aza‐2‐azoniaallene hexachloroantimonates 4 and 6, respectively. Reaction of 2 with aminoacetone or chloroethylamine afforded the acylated 5‐thio‐β‐d‐glucopyranosyl‐4‐imidazoline‐2‐thione nucleoside 16 and glucopyranosylamino‐2‐thiazoline derivative 18, respectively. Deblocking of 8, 11, 17 and 19 furnished the free nucleoside analogues 9, 12, 18 and 20, respectively. Analogously, treatment of 2 with chloroethylamine in the 1:2 ratio afforded the thioureylendisaccharide 21. No in vitro antiviral activity against HIV‐1, HIV‐2, human cytomegallovirus (HMCV), has been found for the new synthesized compounds.     

Synthesis of 3′-Deoxy-3′ and 5′-Deoxy-5′-[4-(Purin-9-yl/Pyrimidin-1-yl) methyl-1,2,3-Triazol-1-yl]thymidine via 1,3-Dipolar Cycloaddition

Abstract

Synthesis of new 3′-deoxy-3′ and 5′-deoxy-5′-[(4-(purin-9-yl/pyrimidin-1-yl)methyl-1,2,3-Triazol-1-yl]thymidine 8a-g 10a-g from 3′-azido-3′-deoxy-5′-O-monomethoxytrityl-thymidine and 5′-azido-5′deoxythymidine respectively are described. The key step is the 1,3-dipolar cycloaddition between the azido group and N-9/N-1-propargylpurine/pyrimidine derivatives.     

Synthesis of Six-Membered Nucleoside Analogs. Part 1: Pyrimidine Nucleosides Based on the 1,3-Dioxane Ring System

Abstract

The synthesis of pyrimidine nucleosides, cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]uracil (4) cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]thymine (5) and cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]cytosine (6) and their corresponding trans isomers is described. Compound 4 showed modest, selective activity against human immunodeficiency virus in acutely infected primary human lymphocytes.     

Biomesogenic Matrix Systems

Abstract

The bifunctionally reactive nucleoside and distant nucleoside analogs adenosine (Ado), S-[(adenine-9-yl)methoxyethyl]-L-cysteine (Na-salt) (cysA) and 9-vinyladenine (vA) in aqueous solutions assemble on complementary polyuridylic acid templates to form complex lyomesophases. The systems are investigated by polarizing microscopy, differential scanning calorimetry (DSC) and ¹H- and ³¹P-nmr spectroscopies, assisted by molecular modeling studies. The results indicate the importance of biomesogenic (pre)ordering in nucleic acid native and artificial matrix reactions.     

Evaluation of Oligonucleotides Containing Two Novel 2′-O-Methyl Modified Nucleotide Monomers: A 3′-C-Allyl and a 2′-O-3′-C-Linked Bicyclic Derivative

Abstract

The two ribo-configured nucleosides 1-(3-C-allyl-2–0-methyl-β-D-ribo-pentofuranosyl)thymine 3 and (1S,5R,6R,8R)-5-hydroxy-6-(hydroxymethyl)-1-methoxy-8-(thymin-1-yl)-2,7-dioxabicyclo[3.3.0]octane 6 have been transformed into their corresponding phosphoramidites, 5 and 8 respectively, and used as building blocks for the synthesis of modified oligonucleotides. The oligonucleotides were shown to hybridize with decreased binding affinity towards complementary single stranded DNA and RNA.     

Cyclohexenyl Nucleosides and Related Compounds

Abstract

Cis and trans-1-(4-hydroxy-2-cyclohexenyl)- and 1-(2-hydroxy-5-cyclohexenyl) thymines were obtained by stereospecific routes. Oxidation of the 1, 4-products afforded 1-(4-oxo-2-cyclohexenyl)thymine, the carbocyclic analog of a reportedly antiviral ketopyranosyl nucleoside. Exclusive 1, 6-conjugate addition occurred with heterocyclic bases and methyl 1, 3-cyclohexadiene-1-carboxylate. Reduction of the thymine adduct gave 1-(4-hydroxymethyl1-3-cyclohexenyl)thymine. Michael-type addition provided a direct route to 3-oxocycloalkyl nucleosides, and lactone nucleosides resulted from addition of bases to α-methylene-γ-butyrolactone. Anti-HIV screening revealed no activity for the new compounds.     

Synthesis of Novel Branched Nucleoside Dimers Containing a 1,2,3-Triazolyl Linkage

Abstract

Three branched nucleoside dimers containing a 1,2,3-triazole linkage have been synthesized using 1,3-dipolar cycloaddition of N-3 or C-5 acetylene nucleosides with 3′-azido-3′-deoxythymidine.     

Compounds similar to acyclovir. III. Synthesis of acyclic analogs of 5'-deoxynucleosides

A convenient method has been proposed for the synthesis of 1,2-dihydroxy-4-oxahex-3-yl and 1-hydroxy-4-oxahex-3-yl derivatives of guanine, adenine, thymine and cytosine, acyclic nucleoside analogues lacking the 3'--4' bond.     

Synthesis of 4-Deoxy-4-C-hydroxymethyl-α-L-Lyxo-Pyranosyl Thymine

Abstract

The synthesis of 1-[4-deoxy-4-C-hydroxymethyl-α-L-lyxopyranosyl]thymine has been accomplished by two synthetic routes both starting from methyl 2, 3-O-isopropylidene-β-D-ribopyranoside. The first route makes use of a ring opening, ring closure reaction sequence to increase the proportion of the desired L-isomers. The second route utilizes the soft nucleophilic character of malonyl anions and ozonolytic cleavage of enol ether to introduce the branched chain. The newly obtained pyranosyl nucleoside obtains a ⁴C₁ conformation with an equatorially oriented thymine moiety.     

Synthesis of the four 1-(1-deoxy-D-pentitol-1-yl)thymines and conformational properties of the acyclic sugar chain

Acetylated D-pentose diethyl dithioacetals were coupled by way of 1-bromo-1-ethylthio derivatives with 2,4-bis(trimethylsilyl)thymine to afford diastereomeric pairs of acyclic-sugar nucleoside analogues bearing a thymin-1-yl and an ethylthio group at C-1. Free-radical desulfurization by the action of tributylstannane removed the ethylthio group to afford the corresponding acetylated 1-(1-deoxy-d-pentitol-1-yl)thymines and subsequently the free title compounds in the arabino, lyxo, ribo, and xylo series. Conformations of the intermediates and products were studied in detail and the final products were evaluated for their potential as agents active against plant viruses and rice blast fungus.     

A Zero-Length Diazirine Photoactive Nucleoside

Abstract

The scheme of synthesis which allows to obtain 5-(3H-diazirin-3-yl)-2′-deoxyuridine as the zero-length photoactive nucleoside is described.