Synthesis and Properties of O-β-D-Ribofuranosyl-(1″-2′)-Adenosine-5″-O-Phosphate and Its Derivatives

Abstract

The synthesis of O-β-D-ribofuranosyl-(1″-2′)-adenosine-5″-O-phosphate and its suitably protected derivative for oligonucleotide synthesis have been developed.     

Synthesis and Herbicidal Activity of Phenoxypropionic Acid Derivatives with Imidazo[1,2-α]pyridine Moiety

Phenoxypropionic acid derivatives (Ia-s) with an imidazo[1,2-a]pyridine moiety were synthesized and their herbicidal activities were examined. The activities were affected dramatically by the substituents on the imidazo[1,2-a]pyridine ring, and good substituents to enhance the herbicidal activity were a cyano group at the 3-position and a chlorine atom at the 6-position. Among the compounds, n-propyl 2-[4-(6-chloro-3-cyano-2-imidazo[1,2-a]pyridinyloxy)phenoxy]propionate(Iq) was most active against gramineous weeds and the activity was comparable to that of the commercial herbicide fluazifop-butyl.     

Synthesis and Properties of Phosphorylated 3′-O-β-D-Ribofuranosyl-2′-deoxythymidine

Abstract

A strategy was developed for the synthesis of 3′-O-β-D-ribofuranosyl 2′-deoxythymidine derivatives using three different protecting groups, which allows the synthesis of a phosphoramidite building block for oligonucleotide synthesis. Likewise the 5′-O- and 5″-O-phosphorylated analogues were synthesized and their conformation was determined using NMR spectroscopy.     

X-Ray Crystallographic and Kinetic Analysis of Human Purine Nucleoside Phosphorylase Complexes with 1-β-D-Ribofuranosyl-1,2,4-triazole-3-carobxamide and 1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboxamidine

Abstract

The three-dimensional structures of the complexes between human erythrocytic purine nucleoside phosphorylase (PNP) and both 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin) and 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine (TCNR) have been determined using X-ray crystallographic techniques. The structures have been refined at 2.9 Å resolution using simulated annealing and conjugate-gradient minimization techniques to an R value of 21.8% for ribavirin and 20.8% for TCNR. Ribavirin and TCNR are truncated nucleosides corresponding to adenosine and inosine, respectively, and are of potential interest as PNP inhibitors. Kinetic parameters have been determined for recombinant wild-type PNP and for a mutant PNP in which Asn 243 is converted to Asp. The K_i value for ribavirin is 4.9 mM with wild-type PNP and 4.7 mM with the Asn243Asp mutant, while the K_i values for TCNR are 17.6 μM and 3.8 μM with wild-type and mutant, respectively. X-ray crystallographic studies showed that the binding geometry for both of these substrate analogues was similar to that seen for natural substrates. The glycosidic torsion angles (χ) were ?34° for ribavirin and ?39° for TCNR which are in good agreement with values seen for other studied nucleoside complexes with PNP, but which are unusual when compared to those seen for free nucleic acid derivatives. Based upon the three-dimensional structure, interactions of Asn 243 and Glu 201 with a protonated carboxamidine of TCNR explain the stronger inhibition of PNP observed for TCNR over ribavirin.     

The Preparation and Utility of 5-β-D-Ribofuranosyl-(2H)-Tetrazole as a Key Synthon for C-Nucleoside Chemistry

Abstract

A synthesis of 5-β-D-ribofuranosyl-2H-tetrazole (1) 5-β-D.-ribofuranosyl-oxadiazoles, diethyl-δ2 -pyrazoline-4,5-dicarboxylate and diethylpyrazole-4,5-dicarboxylate derivatives is described. Ring transformations of1, has been investigated in an effort to establish the stability of this synthon for further use in dipolar cycloaddition reactions.     

Synthesis of 1-[3-deoxy-β-D-psicofuranosyl]uracil and related compounds

D-Fructose affords on treatment with cyanamide 2-amino-beta-D-fructofuro[2',3':3,4]-oxazoline which is not isolated but transformed directly by the reaction with ethyl propiolate into O(2,3)-anhydro-2-[beta-D-fructofuranosyl]uracil. This compound is benzoylated to the 1',4',6'-tri-O-benzoyl derivative by the action of benzoyl cyanide and triethylamine. On treatment with hydrogen chloride/dimethylformamide, the latter intermediate is converted to the 1-[1,4,6-tri-O-benzoyl-3-chloro-3-deoxy-beta-D-psicofuranosyl]uracil 1',4',5'-tribenzoate from which the title nucleoside derivative is obtained by methanolysis.     

6β-[2-Methylbutanoyloxy]tropan-3α-ol,a new alkaloid from Datura ceratocaula structure and biosynthesis

6β-[2-methylbutanoyloxy]tropan-3α-ol, a new alkaloid, has been isolated from the aerial parts of Datura ceratocaula (Solanaceae). Its chemotaxonomic significance within the genus is discussed. Biosynthetically, the 2-methylbutanoyl moiety is derived from L-isoleucine.     

Synthesis of Derivatives of 3-Methylxantheve and 1-Methyl-3-Isobutylxanthine 7-β-D-Ribofuranosides

Abstract

Methods of synthesis of 7–(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)-8-chloro-3-methylxanthine (5a) and l-methyl-3-isobutylxanthine (5b) were reported. Further nucleophilic displacement of chlorine has provided the corresponding 8-alkylamino and 8-benzylamino derivatives (6a,b-9a,b). Several 5′-acyl analogues of 3-methylxanthine-7–β-D-ribofuranoside (15–18) were synthesized using 7–(2′,3′-di-O-isopropylidene-β-D-ribofuranosyl)-3-methylxanthine (10) as intermediate.     

Preparation and Properties of the 5,6- and 4,6(5,7)-Dinitro Derivatives of Benzimidazole and their 1-β-D-Ribofuranosides

Abstract

Nitration of benzimidazole leads to the formation of the two isomeric 5,6- and 4,6(5,7)-dinitrobenzimidazoles, which may be isolated by fractional crystallization. The chloromercury salts of these were employed to synthesize the corresponding 1-β-D-ribofuranosides, unequivocally characterized by ¹H NMR spectroscopy. Reference is made to the biological significance of these results.     

Crystal structure and properties of [TTF]2.5[V(mnt)3 ]·0.5CH2ClCH2Cl[TTF = tetrathiafulvalene and mnt = 1,2-dicyanoethylene-1,2-dithiolate(2−)]

The title salt was obtained by a reaction of [TTF]₃ [BF₄]₂ (TTF = tetrathiafulvalene) with [NMe₄]₂ [V(mnt)₃] [mnt = 1,2-dicyanoethylene-1,2- dithiolate(2−)] in a mixture of 1,2-dichloroethane and acetonitrile (3:2 ν/ν). A single crystal X-ray analysis of it revealed a TTF columnar structure consisting of both TTF⁰ and the TTF^·+ radical cation and the distorted octahedral geometry of the [V(mnt)₃]²⁻ anion. The salt crystallizes in a monoclinic system, space group C2/c with unit cell constants a = 25.428(3), b = 12.434(2), c = 25.477(3) Å, β = 92.428(3)° and Z = 8. The structure was solved by the direct method and refined, on the basis of 3854 [|F_o| > 3σ(F)] observed data, to an R value of 0.078. The salt e`xhibits electrical conductivity of 1.7 x 10⁻⁴ S cm⁻¹ at 25°C for a compacted pellet.     

Preparation and structural determination of methyl 4,6-O-benzylidene-2,3-dideoxy-β-d-erythro-hexopyranosid[2,3-d]triazole and of its adducts with 3-nitrohex-2-enopyranosides

A 3-nitrohex-2-enopyranoside whose C-1 atom was mostly deuterated was prepared from (1S)-1,5-anhydro-d-(1,²H)glucitol and subjected to an addition reaction with methyl 4,6-O-benzylidene-2,3-dideoxy-β-d-erythro-hexopyranosid-[2,3-d]-triazole, derived from the nitro alkene with lithium azide. The structure of the adducts was, by ¹H-n.m.r. spectroscopy, assigned the d-gluco configuration for the nitro sugar moiety.     

Synthesis of 1-(β-D-Ribofuranosyl)Thieno[3,2-d] Pyrimidine-2,4-Dione and 4-Substituted Derivatives

Abstract

Regiospecific ribosylation of the bis(trimethylsilyl) derivative of thieno[3,2-d]pyrimidine-2,4-dione in the presence of a Lewis acid followed by debenzoylation has afforded 1-(β-D-ribofuranosyl)thieno[3,2-d]pyrimidine-2,4-dione, a uridine analogue. The site of ribosylation and anomeric configuration of this N-nucleoside were established by NMR and UV. Thiation of the β-anomer was followed by treatment with methanolic ammonia to afford 4-amino-1-(β-D-ribofuranosyl)thieno [3,2-d]pyrimidin-2-one, a cytidine analogue.     

Synthesis and Biologic Evaluation of 8-Substituted Derivatives of Nebularine (9-β-D-Ribofuranosylpurine)

Abstract

A series of 8-substituted purine ribonucleosides were prepared from 2′, 3′, 5′-tri-O-acetyl-8-bromoadenosine and evaluated for cytotoxicity and antiviral activity. Four of these nucleosides (6b-9b) were significantly toxic to both HEp-2 and L1210 cells in culture but the most cytotoxic one (9b) was inactive against the P388 leukemia in mice. None of these nucleosides showed significant antiviral activity against Herpes Simplex 1 or 2, vaccinia, or influenza A.     

6-chloro-3-β-d-erythrofuranosyl-l-phenyl- and -l-p-tolylpyrazolo-[3,4-b]quinoxaline

The C-nucleoside analogs 6-chloro-3-β-d-erythrofuranosyl-l-phenylpyrazolo-[3,4-b]quinoxaline (5) and 3-β-d-erythrofuranosy]-l-p-tolylpyrazolo[3,4-b]quinoxaline (10) were prepared by dehydration of the polyhydroxyalkyl chain of 6(7)-chlorolo-phenyl-3-(d-arabino-tetritol-l-yl)-pyrazolo(3,4-b]quinoxaline and 3-(d-arbino-tetritol-l-yl)-l-p-tolylpyrazolo[3,4-b]quinoxaline, respectively. The structure and anomeric configuration of 5 and 10 were determined by high-resolution, n.m.r. spectroscopy. The mass spectra and biological activities of some of these compounds are discussed.     

Fruit and vegetable and fried food consumption and 3-(2-deoxy-β-D-erythro-pentafuranosyl)pyrimido[1,2-α] purin-10(3H)-one deoxyguanosine adduct formation

Diet has been shown to modulate M(1)dG adduct, a biomarker of oxidative stress and lipid peroxidation. Thus, we analysed the association between diet and M(1)dG in 120 controls and 67 Map Ta Phut industrial estate workers in Rayong, Thailand, to evaluate the influence of fruit and vegetables, and fried and charcoal-grilled/barbecued food consumption on M(1)dG. M(1)dG was decreased in controls reporting to consume 14-17 servings/week of fruit and vegetables (mean ratio [MR]= 0.35, CI 0.18-0.69, p< 0.05). Conversely, a non-statistically significant M(1)dG increment was detected in controls consuming 9-18 servings/week of fried food (MR = 1.33, CI 0.88-2.00, p = 0.168). No effect of charcoal-grilled/barbecued food was found. No effect of diet was observed in workers. An association with smoking was observed in controls (MR = 1.88, CI 1.14-3.10, p < 0.05), but not in workers. M(1)dG can induce mutations and/or methylation changes within the promoter regions of cancer-related genes, thus promotion of healthy eating practices should be recommended.     

Synthesis of 3-O-(2-acetamido-2-deoxy-3-O-β-d-galactopyranosyl-β-d-galactopyranosyl)-1,2-di-O-tetradecyl-sn-glycerol

Stereo- and regio-selective synthesis of 3-O-(2-acetamido-2-deoxy-3-O-β-d- galactopyranosyl-β-d-galactopyranosyl)-1,2-di-O-tetradecyl-sn-glycerol by use of 1,2-di-O-tetradecyl-3-O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-d-galactopyranosyl)-sn-glycerol as a key intermediate is described.     

Sterol chemical configuration and conformation influence the thermotropic phase behaviour of dipalmitoylphosphatidylcholine mixtures containing 5β-cholestan-3β- and -3α-ol

We report here our differential scanning calorimetry measurements investigating the thermotropic phase behaviour of binary dipalmitoylphosphatidylcholine (DPPC)/sterol mixtures containing two saturated sterols with different ring configurations (5β-H and either 3α-OH or 3β-OH). These measurements differ in the proportions of sharp and broad components in the heating endotherms, representing the melting of the sterol-poor and sterol-rich lipid micro-domains of the DPPC bilayer, respectively. Our results suggest that the 5,10-cis ring configuration of both saturated sterols and the ring A conformations have the greatest influence on DPPC bilayer properties, most likely by inducing small increases in the mean area/molecule as compared to cholesterol. However, the C3-OH orientation also influences sterol miscibility, likely due to variations in the strength and number of interfacial H-bonds with changes in molecular area, which in turn probably reflect the depth of the sterol in the DPPC bilayer. This influence of C3-OH orientation is significantly greater than was observed in our earlier study of cholesterol/- and epicholesterol/DPPC mixtures. Overall, our results show that both saturated and unsaturated 3α-ols are less miscible than the corresponding 3β-ols, but that the presence of a Δ⁵ double bond can improve the sterol miscibility in the DPPC bilayer at high sterol concentrations.     

Synthesis of Galβ1-4GlcNAcβ- and Galβ1-3GalNAcα-O-L-serine Derivatives employing glycosidases

A new approach for the highly specific preparation of L-serine conjugates of lactosamine and Gal1-3GalNAc is described. Thus, the L-serine derivative of lactosamine Gal1-4GlcNAc-O-(N-Z)-Ser-OEt, was obtained from lactose, employing GlcNAc-O-(N-Z)-Ser-OEt as acceptor and a yeast -galactosidase as catalyst Galp 1-3GalNAc-O-(N-Alloc)-Ser-OMe was obtained from lactose, employing GalNAc-O-(N-Alloc)-Ser-OMe as acceptor and -galactosidase from bovine testes as catalyst.     

Nucleosides. LXII. Synthesis of 6-Methyl-8-(2-deoxy-β-D-ribofuranosyl)-isoxanthopterin and Derivatives

Abstract

The syntheses of 6-methyl-8-(2-deoxy-ß-D-ribofuranosyl)isoxanthopterin (21) and its protected 3′-O-phosphoramidite 23 were achieved from 6-methyl-2-methylthio-8-(2-deoxy-3,5-di-O-p-toluoyl-ß-D-ribofuranosyl)-3H,8H-pteridine-4,7-dione (8) in several steps. The new building block for oligonucleotide syntheses is highly fluorescent and can be considered as a substitute for 2′-deoxyguanosine.