Synthesis of 1-(β-D-Glycopyranosyl)-3-Deazapyrimidines from 2-Hydroxy and 2-Mercaptopyridines

Abstract

The synthesis of new 4- and 5-substituted-3-cyanopyridine nucleosides has been performed by reacting the silylated pyridines and penta-O-acetyl-α -D-glycopyranose in dichloroethane in the presence of SnCl₄. The free nucleosides were tested for their potential activity against HIV and different types of tumor.     

Structure,energetics and properties of some molecules with potent anti-HIV activity: a theoretical study

Density functional theory (DFT; B3LYP) and Hartree–Fock (HF; 3-21G, 6-31G(d) and 6-311G(d,p)) calculations with complete geometry optimisations are carried out in the ground state on five 6-aminoquinolone derivatives, which have been proved to be highly effective in inhibiting HIV replication, to study their structures, energetics and HOMO–LUMO correlation with physiological action. The gas-phase calculations and single-point polarisable continuum model water-phase calculations show that the molecules are highly effective in inhibiting HIV replication, which is in excellent agreement with the experiment. Structural features, energies, charge densities and HOMO–LUMO correlation have been found to substantiate the experimental findings. Compound 4 (pyrazine) shows some special features in DFT calculations which are not found in HF calculations. In the present series, HF results are more reliable as expected.     

Synthesis and Biological Activity of Modified Thiopyrimidine Nucleosides

Abstract

N³ -β-D-glucopyranosyl, galactopyranosyl and xylopyranosyl 6-methyl-2-methylthiouracil and their 5-bromo derivatives have been synthesized by coupling an a-acetobromosugar with the corresponding thiouracil. The new modified thiouridine analogues were evaluated for their inhibitory activity against Human Immunodeficiency Virus (HIV) replication in MT-4 cells as well as for their cytotoxicity.     

Relationship Between Conformation and Antiviral Activity-III. 3′-Azidothymidine (AZT) and 3′-Azido-2′, 3′-dideoxy-5-hydroxymethyluridine

Abstract

3′-Azido-2′,3′-dideoxy-5-hydroxymethyluridine (AZHMddUrd) was synthesized to improve the potency of 5-hydroxymethyl-2′-deoxyuridine (HMdUrd) against human immunodeficiency virus (HIV). AZHMddUrd was a very poor inhibitor of HIV replication (ED₅₀ >200 μM) and was also nontoxic up to 400 μM (highest concentration tested) to HT4-6C (HeLa CD₄) cells. AZT was phosphorylated by human cellular thymidine kinase. In contrast, AZHMddUrd and HMdUrd were poor substrates for the kinase. The relationship between molecular conformation and antiretroviral activity for 3′-azidothymidine (AZT), HMdUrd and AZHMddUrd is discussed.     

Metabolism of O6-Propyl and N6-Propyl-carbovir in CEM Cells

Abstract

The metabolism of O⁶-propyl-carbovir and N⁶-propyl-carbovir, two selective inhibitors of HIV replication, has been evaluated in CEM cells. Both compounds were phosphorylated in intact cells to carbovir-5′-triphosphate. The metabolism of these two agents was inhibited by deoxycoformycin and mycophenolic acid, but not erythro-9-(2-hydroxy-3-nonyl)adenine. No evidence of the 5′-triphosphate of either compound was detected in CEM cells.     

Structures of the novel diterpene glycosides from Stevia rebaudiana

From the commercial extract of the leaves of Stevia rebaudiana, two new diterpenoid glycosides were isolated besides the known steviol glycosides including stevioside, rebaudiosides A–F, rubusoside, and dulcoside A. The structures of the two new compounds were identified as 13-[(2-O-6-deoxy-β-d-glucopyranosyl-β-d-glucopyranosyl)oxy] ent-kaur-16-en-19-oic acid β-d-glucopyranosyl ester (1), and 13-[(2-O-6-deoxy-β-d-glucopyranosyl-3-O-β-d-glucopyranosyl-β-d-glucopyranosyl)oxy] ent-kaur-16-en-19-oic acid β-d-glucopyranosyl ester (2), on the basis of extensive NMR and MS spectral data as well as chemical studies.     

New triterpene oligoglycosides from the Caribbean sponge Erylus formosus

Seven new triterpene glycosides, erylosides R₁ (1), T₁ (3), T₂ (4), T₃ (5), T₄ (6), T₅ (7), and T₆ (8) along with the known formoside (2) were isolated from the sponge Erylus formosus collected along the Caribbean coast of Mexico. Glycoside 1 was determined as a trisaccharide, glycoside 2 as a tetrasaccharide while glycosides 3–8 were hexasaccharide. Their carbohydrate chains were unprecedented and have never been found in oligosaccharides from other biological sources, except Erylus spp. Three carbohydrate chains in the glycosides 3 and 6, 4 and 7, 5 and 8 correspondingly are new. The glycosides 1–5 have penasterol as aglycone while glycosides 6–8 proved to be glycoconjugates of 24-methylene-14-carboxy-lanost-8(9)-en-3β-ol.     

Microwave-Assisted Synthesis and Anti-HIV Activity of New Acyclic C-Nucleosides of 3-(D-Ribo-Tetritol-1-yl)-5-Mercapto-1,2,4-Triazoles. Part 1

Microwave-assisted synthesis of novel acyclic C-nucleosides of 6-alkyl/aryl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5–12) and the 6-aryl-thiomethyl analogues 25–27 has been described. Deblocking of 5–12 and 25–27 afforded the free acyclic C-nucleosides 13–20, and 28–30, respectively. All of the synthesized compounds showed no inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 6-(3,4-dichlorophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (6) is a potent inhibitor, in vitro, of the replication of HIV-2. These results suggest that compound 6 should be considered as a new lead in the development of antiviral agent.     

Minor diterpenoid glycosides from the leaves of Stevia rebaudiana

From the commercial extract of the leaves of Stevia rebaudiana, three new diterpenoid glycosides were isolated besides eight known steviol glycosides including stevioside, rebaudiosides A–F and dulcoside A. The structures of the three compounds were identified as 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-kaur-16-en-18-oic acid-(6-O-β-d-xylopyranosyl-β-d-glucopyranosyl) ester (1), 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-17-hydroxy-kaur-15-en-18-oic acid β-d-glucopyranosyl ester (2), and 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-17-oxo-kaur-15-en-18-oic acid β-d-glucopyranosyl ester (3) on the basis of extensive NMR and MS spectral studies. Another known diterpenoid glycoside, 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-kaur-15-en-18-oic acid β-d-glucopyranosyl ester (4) was also isolated and its complete NMR spectral assignments were made on the basis of COSY, HSQC and HMBC spectral data.     

New Steroidal Glycosides from Rhizomes of Clintonia udensis

A total of 10 steroidal glycosides, together with three new spirostanol glycosides (6–8), a new furostanol glycoside (9), and a new cholestane glycoside (10), were isolated from the rhizomes of Clintonia udensis (Liliaceae). The structures of the new compounds were determined on the basis of extensive spectroscopic analyses, including 2-D nuclear magnetic resonance (NMR) data, and of hydrolytic cleavage followed by chromatographic or spectroscopic analyses. The isolated glycosides were evaluated for their cytotoxic activity against HL-60 leukemia cells. Spirostanol glycosides 1 and 2, and furostanol glycoside 4 showed cytotoxic activity with IC₅₀ values of 3.2±0.02, 2.2±0.12, and 2.2±0.06 μg/ml, respectively. Neither the spirostanol and furostanol saponins with a hydroxy group at C-1 (6 and 9) and C-12 (7 and 8) nor cholestane glycosides (5 and 10) exhibited apparent cytotoxic activity at a sample concentration of 10 μg/ml.     

Synthesis and Biological Activity of 4-Amino-1-(β-D-ribofuranosyl)imidazo[4,5-d]pyridazin-7-one

Abstract

The Lewis acid catalyzed ribosylation of 5(4)-cyano-4(5)-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-imidazole (2) with 1-O-acetyl-2,3,5-tri-O-benzoyl-B-D-ribose gave only 4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(2,3,5-tri-O-benzoy 1-B-D-ribofuranosyl)imidazole-5-carbonitrile (3). Treatment of 3 with methanolic ammonia gave 4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(6-D-ribofuranosyl)imidazole-5-carbonitrile (4). Treatment of 4 with hydrogen peroxide in ammonia gave -(5-methyl-1,2,4-oxadiazol-3-yl)-1-(B-D-ribofuranosyl)imidazole-5-carboxamide (5). When 5 was treated with sodium hydride in dimthyl-sulfoxide a rearrangement (mononuclear heterocyclic rearrangement, m.h.r.) occurred to give a modest 17% yield of 4-acetamido-1-(B-D ribofuranosyl)imidazo[4,5-d]pyridazin-7-one (6). Treatment of 6 with aqueous ammonia gave4-amino-l-(B-D-ribofuranosyl)imidazo[4,5-d]pyridazin-7-one (1). The synthesis of compound 1 using the m.h.r. for the preparation of a single regioisomer of the imidazo[4,5-d]pyridazin-7-one ring system, has demonstrated the potential of this methodology. Neither compound 5 nor 6 affected the growth or replication of human foreskin fibroblasts (HFF cells) or human cytomegalovirus (HCMV). In contrast, compound 1 inhibited the replication of HCMV (IC₅₀=29 μM) but produced visual cytotoxicity in uninfected HFF cells (IC₅₀=70μM). Compound 1 also inhibited the proliferation of L1210 murine leukemic cells (IC₅₀=25μM), whereas the precursors 4 and 6 did not.     

SYNTHESIS AND ANTIVIRAL EVALUATION OF N-GLYCOSIDES DERIVED FROM 6-AMINO-3-ARYL-2-METHYL-4-(3H)-QUINAZOLINONES

Reaction of monosaccharides (D-glucose, D-galactose, D-xylose or L-arabinose) with 6-amino-3-aryl-2-methyl-4-(3H) quinazolinones (1a–c) in boiling methanol yielded the corresponding N-glycopyranosides 3a–c, 4a–c, 5a,b and 6a,b. The N-glycopyranosides 3a–c, 4a–c, 5a,b and 6a,b were acetylated with acetic anhydride and pyridine to give the corresponding acetate derivatives 7a–c, 8a–c, 9a,b and 10a,b. The structures of all these glycosides were assessed by elemental analysis, IR, NMR and mass spectra. Some of these products were tested for anticancer and anti-AIDS activity.     

Structure and Hypotensive Effect of Flavonoid Glycosides in Kinkan (Fortunella japonica) Peelings

An attempt was made to isolate the hypotensive substances from a hot water extract of kinkan. Eight flavonoid glycosides were isolated by repeated chromatography and by gel filtration after extracting with n-butanol and treating with lead subacetate. Their structures were established to be 6,8-di-C-glucosylapigenin (1), 3,6-di-C-glucosylacacetin (2), 2″-O-α-l-rhamnosyl-4′-O-methyl-vitexin (3), 2″-O-α-l-rhamnosyl-4′-O-methylisovitexin (4), 2″-O-α-l-rhamnosylvitexin (5), 2″-O-α-l-rhamnosylorientin (6), 2″-O-α-l-rhamnosyl-4′-O-methylorientin (7) and ponicilin (8) by UV. MS, ¹-NMR and ¹³C-NMR spectroscopy, and by sugar analysis. Each component was intravenously injected in SHR-SP (0.5 ~ 1.0 mg/100 g of body weight), 1, 2, 5 and 6 were found to lower the rat blood pressure.

Among these compounds, 2, 3, 4, 6 and 7 were new flavone glycosides.     

Two new anti-plasmodial flavonoid glycosides from Duranta repens

The CHCl₃-soluble fraction of the whole plant of Duranta repens showed anti-plasmodial activity against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum, with IC₅₀ values of 8.5?±?0.9 and 10.2?±?1.5?μg/mL, respectively. From this fraction, two new flavonoid glycosides, 7-O-α-d-glucopyranosyl-3,4′-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (1) and 7-O-α-d-glucopyranosyl(6′′′-p-hydroxcinnamoyl)-3,4′-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (2), along with five known flavonoids, 3,7,4′-trihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (3), 3,7-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6,4′-trimethoxyflavone (4), 5,7-dihydroxy-3′-(2-hydroxy-3-methyl-3-butenyl)-3,6,4′-trimethoxyflavone (5), 3,7-dihydroxy-3′-(2-hydroxy-3-methyl-3-buten-yl)-5,6,4′-trimethoxyflavone (6), and 7-O-α-d-glucopyranosyl-3,5-dihydroxy-3′-(4′′-acetoxy-3′′-methylbutyl)-6,4′-dimethoxyflavone (7), have been isolated as anti-plasmodial principles. Their structures were deduced by spectroscopic analysis including 1D and 2D NMR techniques. The compounds (1–7) showed potent anti-plasmodial activities against D6 and W2 strains of Plasmodium falciparum, with IC₅₀ values in the range of 5.2–13.5?μM and 5.9–13.1?μM, respectively.     

Synthesis of 3′-Deoxy-3′-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine via 1,3-Dipolar Cycloaddition

Abstract

The synthesis of new 3′-deoxy-3′-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine 6a–f, from 3′-azido-3′-deoxy-5′-O-monomethoxytrityl-thymidine is described. The key step is the 1,3-dipolar cycloaddition between the azido group of the protected AZT 3 and N-1-propargylpyrimidine derivatives 2a–f. All new derivatives 6a–f were evaluated for their inhibitory effects against the replication of HIV-1 (IIIB), HIV-2 (ROD). No marked activity was found.     

Structures of the novel α-glucosyl linked diterpene glycosides from Stevia rebaudiana

From the commercial extract of the leaves of Stevia rebaudiana, two new minor diterpene glycosides having α-glucosyl linkage were isolated besides the known steviol glycosides including stevioside, steviolbioside, rebaudiosides A–F, rubusoside and dulcoside A. The structures of the two compounds were identified as 13-[(2-O-(3-α-O-d-glucopyranosyl)-β-d-glucopyranosyl-3-O-β-d-glucopyranosyl-β-d-glucopyranosyl)oxy] ent-kaur-16-en-19-oic acid β-d-glucopyranosyl ester (1), and 13-[(2-O-β-d-glucopyranosyl-3-O-(4-O-α-d-glucopyranosyl)-β-d-glucopyranosyl-β-d-glucopyranosyl)oxy] ent-kaur-16-en-19-oic acid β-d-glucopyranosyl ester (2), on the basis of extensive NMR and MS spectral data as well as chemical studies.     

SYNTHESIS AND ANTI-HIV ACTIVITY OF [D4U]-[TROVIRDINE ANALOGUE] AND [D4T]-[TROVIRDINE ANALOGUE] HETERODIMERS AS INHIBITORS OF HIV-1 REVERSE TRANSCRIPTASE

ABSTRACT

A series of eleven heterodimers containing both a nucleoside analogue (d4U, d4T) and a non-nucleoside type inhibitor (Trovirdine analogue) were synthesized and evaluated for their ability to inhibit HIV replication. Unfortunately, the (N-3)d4U-Trovirdine conjugates (9a–e) and (N-3)d4T-Trovirdine conjugates (10a–f) were found to be inactive suggesting that the two individual inhibitor compounds do not bind simultaneously in their respective sites.     

Inhibitory Effects of 1-Deazaadenosine Analogues on HIV Replication and Adenosine Deaminase

Abstract

A series of 2′,3′-dideoxy-N⁶-(cyclo)alkyl-1-deazaadenosine derivatives were synthesized starting from 2,6-dichloro-1-deazapurine (9). The new nucleosides proved to be good inhibitors of HIV-1 replication, the most active being the 2′,3′-dideoxy-2-chloro-N⁶-cycloctyl-1-deazaadenosine (14h, ED₅₀ = 0.4 μ).     

Studies on Nucleoside Analogs. XXV.1) Synthesis of 5, 7-Dioxopyrimido[5,4-e]-AS-Triazine Glycosides

Abstract

The reaction of glycosyl isothiocyanates (la, b, c, d, e) with 5,6-diamino-1-3-dimethyluracil gave the respective 1-glycosyl-3-(6-amino-1, 3-dimethyl-2, 4-dioxopyrimidine-5-yl) thioureas (2a, b, c, d, e) in excellent yields. Treatment of these thioureas with NBS afforded the respective 5,7-dioxopyrimido-[5,4-e]-as-triazine glycosides (4a, b, c, d, e) in good yields.