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A group of unnatural 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluorobenzenes having a variety of C-5 substituents (H, Me, F, Cl, Br, I, CF3, CN, NO2, NH2), designed as thymidine mimics, were synthesized for evaluation as anticancer and antiviral agents. The coupling reaction of 3,5-bis-O-(p-chlorobenzoyl)-2-deoxy-alpha-D-ribofuranosyl chloride with a...
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... compounds to determine the importance of hydrogen bonding and base stacking in the formation of stable DNA duplex structures. In this respect, the 2,4-difluoro-5-methylphenyl isostere (1b) was designed as an analog of thymidine where F is the isosteric replacement for O, CH replaces NH, and the thymine N1 is replaced by a sp 2 hybridized C (see Fig. 1). F was considered to be the best possible substitution for the carbonyltype O from a structural and electronic viewpoint. Although aromatic-substituted F-atoms can participate in weak intermolecular (6) or intramolecular (7) H -bonds, NMR titration experiments with 2,4-difluorotoluene (the aryl group of 1b) did not ...
Context 2
... (9.2 g, 56%) as white needles, and the α-anomer 7a (6.0 g, 37%) as a light yellow syrup, respectively. The recovered α-anomer 7a (6.0 g) was treated again with BF 3 · Et 2 O (6 mL) in nitroethane (80 mL) to give additional β-anomer 8a (3.5 g, 58%) and α-anomer 7a (2.2 g, 37%) affording collectively β-anomer (12.7 g, 77%) and recovered α-anomer 7a (2.2 g, 13%). Compounds 7b-h and 8b-h were prepared, and α-7b-h were epimerized to β-8b-h, using similar procedures to those described above for 7a and 8a. 5-(3,5-Bis-O-( p-chlorobenzoyl)-2 -deoxy-α-D-ribofuranosyl)-2,4-difluorotoluene (7b) and 5-(3,5-Bis-O-(p-chlorobenzoyl)-2 -deoxy-β-D-ribofuranosyl)-2,4-difluorotoluene (8b). The coupling ...
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Methyl gallate (MG), methyl-3,4,5-trihydroxybenzoate, was highly active against herpes viruses as determined by plaque reduction assay. Herpes simplex virus type 2, MS strain, was sensitive to MG at a mean 50% inhibitory concentration (IC50) of 0.224 micrograms/ml in monkey kidney cells. MG was specific for herpes viruses with the relative sensitiv...
Citations
... Chlorosugar 101 was made as the pure α anomer in three steps from 2′deoxyribose (Scheme 12). 215,216 The condensation was performed in the presence of p-nitrophenol, which led, interestingly, to the stereoselective production of the desired βanomer 103, whereas the combination of p-nitrophenol and pyridine as catalysts led to formation of the α-anomer. Recrystallization from acetic acid gave the pure β-anomer, which was deprotected with methanolic ammonia, concluding the synthesis. ...
Nucleoside, nucleotide, and base analogs have been in the clinic for decades to treat both viral pathogens and neoplasms. More than 20% of patients on anticancer chemotherapy have been treated with one or more of these analogs. This review focuses on the chemical synthesis and biology of anticancer nucleoside, nucleotide, and base analogs that are FDA-approved and in clinical development since 2000. We highlight the cellular biology and clinical biology of analogs, drug resistance mechanisms, and compound specificity towards different cancer types. Furthermore, we explore analog syntheses as well as improved and scale-up syntheses. We conclude with a discussion on what might lie ahead for medicinal chemists, biologists, and physicians as they try to improve analog efficacy through prodrug strategies and drug combinations.
... Chlorosugar 101 was made as the pure α anomer in three steps from 2′deoxyribose (Scheme 12). 215,216 The condensation was performed in the presence of p-nitrophenol, which led, interestingly, to the stereoselective production of the desired βanomer 103, whereas the combination of p-nitrophenol and pyridine as catalysts led to formation of the α-anomer. Recrystallization from acetic acid gave the pure β-anomer, which was deprotected with methanolic ammonia, concluding the synthesis. ...
Nucleoside, nucleotide, and base analogs have been in the clinic for decades to treat both viral pathogens and neoplasms. More than 20% of patients on anticancer chemotherapy have been treated with one or more of these analogs. This review focuses on the chemical synthesis and biology of anticancer nucleoside, nucleotide, and base analogs that are FDA-approved and in clinical development since 2000. We highlight the cellular biology and clinical biology of analogs, drug resistance mechanisms, and compound specificity towards different cancer types. Furthermore, we explore analog syntheses as well as improved and scale-up syntheses. We conclude with a discussion on what might lie ahead for medicinal chemists, biologists, and physicians as they try to improve analog efficacy through prodrug strategies and drug combinations.
... I-124 radioactivity yield and purity were determined by g-ray spectroscopy (Weinreich and Knust, 2000). 1-(2-Deoxy-b-D-ribofuranosyl)-2,4-difluoro-5-iodoben- zene (dRFIB) was synthesized in 5 steps following the literature method shown in Scheme 1. dRFIB was recovered as a white solid (55 mg, 0.15 mmol; mp 7072 1C); NMR data matched literature values (Wang et al., 2001). 2.1. ...
Iodine-124 was produced via the (124)Te(p,n)(124)I reaction by 15 MeV proton irradiation of an in-house solid mass tellurium dioxide target, using the Tübingen PETtrace (General Electric Medical Systems) cyclotron. 1-(2-Deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene (dRFIB), a stable, non-polar thymidine mimic nucleoside, was synthesized in 5 steps following a literature method, for radioiodination with [(124)I] iodide via isotope exchange in the presence of copper sulphate and ammonium sulphate in methanol-water. The radiolabelling procedure was optimized with respect to temperature, amount of dRFIB, amount of sodium hydroxide and reaction time, to produce radiochemical yields of up to 85% with a 1-h reaction at 140 degrees C. With routine I-124 production of 30 MBq/run, relatively high specific activities, approaching 100 MBq/mmol, can be expected. The activation energy for dRFIB radioiodination was calculated from temperature-time RCY data to be approximately 100 kJ/mol using no-carrier-added [(124)I]iodide.
... Nucleosides, nucleoside analogues and phloridzin were purchased from Sigma (Oakville, ON, Canada). β-DFP-5M 1-(2-deoxy-β-d-ribofuranosyl-2,4-difluoro- 5-methylbenzene) and β-DFP-5I (1-(2-deoxy-β- d-ribofuranosyl)-2,4-difluoro-5-iodobenzene) were synthesized as previously described (Wang et al. 2001). ...
... One millimolar cytarabine was required to produce a detectable inward current, suggesting that it functions as a low-affinity permeant, a conclusion supported by radiotracer flux studies in transfected mammalian cells, where 0.5 mm cytarabine caused only partial inhibition of uridine transport activity (Graham et al. 2000). Two novel pyrimidine nucleoside mimics (β-DFP- 5M and β-DFP-5I) (Wang et al. 2001) also functioned as low-affinity hCNT1 permeants. These compounds demonstrate that the pyrimidine ring is not required for translocation by hCNT1. ...
Human concentrative nucleoside transporter 1 (hCNT1) mediates active transport of nucleosides and anticancer and antiviral nucleoside drugs across cell membranes by coupling influx to the movement of Na(+) down its electrochemical gradient. The two-microelectrode voltage-clamp technique was used to measure steady-state and presteady-state currents of recombinant hCNT1 produced in Xenopus oocytes. Transport was electrogenic, phloridzin sensitive and specific for pyrimidine nucleosides and adenosine. Nucleoside analogues that induced inwardly directed Na(+) currents included the anticancer drugs 5-fluorouridine, 5-fluoro-2'-deoxyuridine, cladribine and cytarabine, the antiviral drugs zidovudine and zalcitabine, and the novel thymidine mimics 1-(2-deoxy-beta-d-ribofuranosyl)-2,4-difluoro-5-methylbenzene and 1-(2-deoxy-beta-d-ribofuranosyl)-2,4-difluoro-5-iodobenzene. Apparent K(m) values for 5-fluorouridine, 5-fluoro-2'-deoxyuridine and zidovudine were 18, 15 and 450 microm, respectively. hCNT1 was Na(+) specific, and the kinetics of steady-state uridine-evoked Na(+) currents were consistent with an ordered simultaneous transport model in which Na(+) binds first followed by uridine. Membrane potential influenced both ion binding and carrier translocation. The Na(+)-nucleoside coupling stoichiometry, determined directly by comparing the uridine-induced inward charge movement to [(14)C]uridine uptake was 1: 1. hCNT1 presteady-state currents were used to determine the fraction of the membrane field sensed by Na(+) (61%), the valency of the movable charge (-0.81) and the average number of transporters present in the oocyte plasma membrane (6.8 x 10(10) per cell). The hCNT1 turnover rate at -50 mV was 9.6 molecules of uridine transported per second.
... rms a stable self-pair and the unnatural self-pairing resulted in an insufficient polymerase chain elongation, which could lead to cytotoxic effects in rapidly proliferating cancer cells. [7] A second group of nonpolar hydrophobic isosteres of pyrimidine nucleoside mimics, based on the pioneering study of Moran et al. [8] has also been synthesized. [9] These compounds were characterized by a 2,4-difluorotoluene moiety as an analogue to thymine in Thd, where F is the isosteric replacement for O, and C – H groups replaces N – H groups (compound JW1, [9] ). In 1-(2-deoxy-b-D-ribofuranosyl)-2,4-difluoro-5- iodobenzene (JW2, 9), the CH 3 group was replaced with I, analogous to iodo-dUrd. T ...
... [7] A second group of nonpolar hydrophobic isosteres of pyrimidine nucleoside mimics, based on the pioneering study of Moran et al. [8] has also been synthesized. [9] These compounds were characterized by a 2,4-difluorotoluene moiety as an analogue to thymine in Thd, where F is the isosteric replacement for O, and C – H groups replaces N – H groups (compound JW1, [9] ). In 1-(2-deoxy-b-D-ribofuranosyl)-2,4-difluoro-5- iodobenzene (JW2, 9), the CH 3 group was replaced with I, analogous to iodo-dUrd. ...
The thymidine mimics isocarbostyril nucleosides and difluorophenyl nucleosides were tested as deoxynucleoside kinase substrates using recombinant human cytosolic thymidine kinase (TK1) and deoxycytidine kinase (dCK), and mitochondrial thymidine kinase (TK2) and deoxyguanosine kinase (dGK). The isocarbostyril nucleoside compound 1-(2-deoxy-beta-D-ribofuranosyl)-isocarbostyril (EN1) was a poor substrate with all the enzymes. The phosphorylation rates of EN1 with TK1 and TK2 were <1% relative to Thd, where as the phosphorylation rates for EN1 were 1.4% and 1.1% with dCK and dGK relative to dCyd and dGuo, respectively. The analogue 1-(2-deoxy-beta-D-ribofuranosyl)-7-iodoisocarbostyril (EN2) showed poor relative-phosphorylation efficiencies (kcat/Km) with both TK1 and dGK, but not with TK2. The kcat/Km value for EN2 with TK2 was 12.6% relative to that for Thd. Of the difluorophenyl nucleosides, 5-(1'-(2'-deoxy-beta-D-ribofuranosyl))-2,4-difluorotoluene (JW1) and 1-(1'-(2'-deoxy-beta-D-ribofuranosyl))-2,4-difluoro-5-iodobenzene (JW2) were substrates for TK1 with phosphorylation efficiencies of about 5% relative to that for Thd. Both analogues were considerably more efficient substrates for TK2, with kcat/Km values of 45% relative to that for Thd. 2,5-Difluoro-4-[1-(2-deoxy-beta-L-ribofuranosyl)]-aniline (JW5), a L-nucleoside mimic, was phosphorylated up to 15% as efficiently as deoxycytidine by dCK. These data provide a possible explanation for the previously reported lack of cytotoxicity of the isocarbostyril- and difluorophenyl nucleosides, but potential mitochondrial effects of EN2, JW1 and JW2 should be further investigated.
Nucleosides have gained significant attention since the discovery of the structure of DNA. Nucleoside analogues may be synthesized through multiple synthetic pathways, however the N-glycosylation of a nucleobase is the most common method. Amongst the different classical N-glycosylation methodologies, the Vorbrüggen glycosylation is the most popular method. This review focuses on the synthesis and therapeutic applications of several FDA approved nucleoside analogues as antiviral and anticancer agents. Moreover, this review also focuses on the potential of these compounds as new antibacterial and anti-Alzheimer's disease agents, offering an overview of the most recent research in these fields.
HCV infections are the leading causes for hepatocellular carcinoma and liver transplantation in the United States. Recent advances in drug discovery have identified direct acting antivirals which have significantly improved cure rates in patients. Current efforts are directed towards identification of novel direct acting antiviral targeting different mechanism of actions which could become part of all oral therapies. We recently disclosed the identification of a novel tricyclic indole derived inhibitors of HCV NS5B polymerase that bound to the enzyme close to the active site. In this manuscript we describe further optimization of potency and pharmacokinetics (PK) of these inhibitors to identify compounds in low nM potency against gt-1b. These analogs also demonstrate excellent PK in rats and monkeys when administered as a dimethyl ethyl amino ester prodrug.
The synthesis of a novel class of 2′-deoxyribonucleosides possessing tropone-fused nitrogen heterocycles as nucleobases was developed. The reaction of alkali metal salts of 1H-cyclohepta[d][1,2,3]triazol-6-one with 2-deoxy-3,5-di-O-(p-toluoyl)-α-d-ribofuranosyl chloride (α-chlorosugar) afforded an anomeric mixture of N1- and N2-coupled glycosylation products. Good stereospecificity in relation to the amount of the β-anomer was achieved in the less polar solvent DME. The reactions of the sodium salt of 1H-cyclohepta[b]pyrrol-8-one and its 3-methyl derivative with an α-chlorosugar in DME gave the β-anomer of the N1-coupled glycosylation products. The glycosylation products were treated with NaOMe in MeOH to produce the desired 2′-deoxyribonucleosides. X-ray structural analyses of the three nucleosides prepared confirmed their anomeric configuration and revealed that their sugars were puckered. The β-anomers of the nucleosides had weak antiviral activities for herpes simplex virus type 1 and herpes simplex virus type 2 in comparison with those of acyclovir (ACV). These nucleosides showed no cytotoxicity on a lung (A549) and two colon (HT-29 and HCT-116) cancer cell lines.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The study and synthesis of C-nucleosides has been extensive owing to their biological activity and potential as drug candidates for antiviral and anticancer therapy. Numerous synthetic strategies have also been investigated in order to optimize yields and stereoselectivity in the glycosylation reaction. Here we review one class of synthetic methods, direct condensation of a pre-formed aglycon unit with an appropriate sugar component.
• 1 Introduction
• 2 Coupling of Ribofuranose Derivatives with Organometallic Reagents
• 3 Heck-Type Coupling Reaction
• 4 Coupling of Protected Ribofuranosyl Chlorides with Organometallic Reagents
• 5 Coupling of 1,4-Ribonolactone Derivatives with Organometallic Reagents
• 6 Coupling Reactions Mediated by Lewis Acids
• 7 Conclusions
