Facile synthesis of O6-alkyl-, O6-aryl-, and diaminopurine nucleosides from 2'-deoxyguanosine

The 3',5'-bis-O-TBDMS derivative of 2'-deoxyguanosine can be converted to its O6-alkyl and O6-aryl ethers as well as to N6-substituted diaminopurine nucleosides in two simple steps. Also described is a novel, nonaqueous, one-step O6-desulfonylation method that leads to deprotection of the carbonyl moiety of 2'-deoxyguanosine.     

Synthesis of pyrene and benzo[a]pyrene adducts at the exocyclic amino groups of 2'-deoxyadenosine and 2'-deoxyguanosine by a palladium-mediated C-N bond-formation strategy

Single-electron oxidation of the carcinogenic hydrocarbon benzo[a]pyrene (BaP) is thought to result in a radical cation intermediate and this species has been proposed to cause alkylation at the nitrogens of the purine nucleobases. Although several different nucleoside adducts have been isolated as arising from this mode of metabolic activation, there are no selective, total syntheses of the stable exocyclic amino group adducts formed by the single-electron oxidation of any hydrocarbon with the purine 2'-deoxynucleosides to date. In this paper we disclose the synthesis of the model adducts N(6)-(1-pyrenyl)-2'-deoxyadenosine and N(2)-(1-pyrenyl)-2'-deoxyguanosine as well as the first synthesis of the carcinogen-linked nucleoside derivatives N(6)-(6-benzo[a]pyrenyl)-2'-deoxyadenosine and N(2)-(6-benzo[a]pyrenyl)-2'-deoxyguanosine via a palladium-mediated C-N bond formation. Two different coupling strategies were attempted: coupling of an aryl bromide with a suitably protected nucleoside and the coupling of an arylamine with a suitable halonucleoside. The former had somewhat limited applicability in that only N(6)-(1-pyrenyl)-2'-deoxyadenosine was prepared by this method; on the other hand, the latter was more general. However, there are noteworthy differences in the amination reactions at the C-6 and C-2 positions. Reactions at the C-6 resulted in the competing formation of a 1:2 amine-nucleoside adduct in addition to the desired monoaryl nucleoside. Such a dimer formation was not observed at the C-2. The C-2 adducts, however, displayed an interesting conformational behavior.     

Pd-Xantphos-catalyzed direct arylation of nucleosides

Direct arylation of the exocyclic amino groups of nucleosides represents a simple approach to N-aryl nucleoside derivatives. To date, one limitation has been that only electron-deficient aryl bromides and triflates possessed adequate reactivity for efficient, direct N-arylation of nucleosides. We demonstrate herein that Pd-Xantphos catalytic systems lead to successful N-arylation of suitably protected 2'-deoxyadenosine and 2'-deoxyguanosine with a wide range of aryl bromides.     

Geopolymer cement–modified carbon paste electrode: application to electroanalysis of traces of lead(II) ions in aqueous solution

Journal of Solid State Electrochemistry - Pb2+ ions were detected on a carbon paste electrode modified with a geopolymer cement. The X-ray pattern and the infrared spectrum of the geopolymer...     

Kaolinite-based Hybrid Material from Interlayer Grafting of 1-(2-Hydroxyethyl)piperazine and Application to the Sensitive Voltammetric Detection of Lead

This work describes the synthesis of an organo-inorganic hybrid material and its application as low-cost electrode material for the electrochemical detection of trace levels of lead in contaminated water. The organo-inorganic hybrid material was obtained by the grafting of 1-(2-hydroxyethylpiperazine) (HEP) in the interlayer space of a natural kaolinite (K). The obtained organokaolinite (K-HEP) was characterized by XRD, FTIR and TGA-DTG techniques. XRD results in particular showed that the structure of the pristine kaolinite was not affected during the synthesis of K-HEP. It was also noticed from ¹³C NMR data that the structure of HEP was preserved during the synthesis process. Taking into account the affinity of the amine group on HEP molecule for lead ions, K-HEP was used to modify the surface of glassy carbon electrode (GCE) (GCE/K-HEP) in order to build a sensor for lead detection. The peak current of Pb(II) recorded on GCE/K-HEP was more intense compared to the signal recorded on bare GCE, and on natural kaolinite film modified GCE. Several parameters that can affect the stripping response were systematically investigated to optimize the sensitivity of the organokaolinite film modified electrode. Under optimized conditions, a calibration curve was obtained in the concentration range from 8.29 to 116.03 ppb; with a detection limit of 0.25 ppb (S/N=3). After the study of some interfering species on the electrochemical response of Pb(II), the developed sensor was successfully applied to the quantification of the same pollutant in tap water and spring water samples.     

The role of the UPS in cystic fibrosis

CF is an inherited autosomal recessive disease whose lethality arises from malfunction of CFTR, a single chloride (Cl-) ion channel protein. CF patients harbor mutations in the CFTR gene that lead to misfolding of the resulting CFTR protein, rendering it inactive and mislocalized. Hundreds of CF-related mutations have been identified, many of which abrogate CFTR folding in the endoplasmic reticulum (ER). More than 70% of patients harbor the DeltaF508 CFTR mutation that causes misfolding of the CFTR proteins. Consequently, mutant CFTR is unable to reach the apical plasma membrane of epithelial cells that line the lungs and gut, and is instead targeted for degradation by the UPS. Proteins located in both the cytoplasm and ER membrane are believed to identify misfolded CFTR for UPS-mediated degradation. The aberrantly folded CFTR protein then undergoes polyubiquitylation, carried out by an E1-E2-E3 ubiquitin ligase system, leading to degradation by the 26S proteasome. This ubiquitin-dependent loss of misfolded CFTR protein can be inhibited by the application of 'corrector' drugs that aid CFTR folding, shielding it from the UPS machinery. Corrector molecules elevate cellular CFTR protein levels by protecting the protein from degradation and aiding folding, promoting its maturation and localization to the apical plasma membrane. Combinatory application of corrector drugs with activator molecules that enhance CFTR Cl- ion channel activity offers significant potential for treatment of CF patients. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).     

Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis

A diastereoselective synthesis of the nucleoside adducts corresponding to a cis ring-opening of the carcinogen (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP DE-2) by 2'-deoxyadenosine and 2'-deoxyguanosine is described. The key intermediate (+/-)-10alpha-amino-7beta,8alpha,9alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene was synthesized by a highly diastereoselective dihydroxylation wherein phenylboronic acid was a water surrogate. The resulting boronate ester was converted to a tetraol derivative in which two of the four hydroxyl groups (trans 7, 8) were protected as benzoate esters while the remaining two (cis 9, 10) were free. The cis glycol entity was then subjected to a reaction with 1-chlorocarbonyl-1-methylethylacetate to yield an intermediate chloro monoacetoxy dibenzoate. Displacement of the halide with azide, complete cleavage of the esters, and catalytic reduction of the azide yielded the requisite amino triol. Fluoride displacement from appropriately protected nucleoside derivatives, 6-fluoropurine 2'-deoxyribonucleoside and 2-fluoro-2'-deoxyinosine, by the amino triol then yielded diastereomeric pairs of diol epoxide-adducted 2'-deoxyadenosine (dA) and 2'-deoxyguanosine (dG) nucleosides. Small aliquots of these adducts were separated for characterization purposes. The present approach provides the first diastereoselective synthesis of the cis adducts of BaP DE-2 with 2'-deoxyguanosine as well as the first synthesis of both dA and dG adducts from a common intermediate. An informative analysis of the 1H NMR spectra of the cis adducts synthesized and comparisons to the trans adducts are reported. To gain insight into the diastereoselectivity in the key dihydroxylation step, a computational analysis, including molecular mechanics (MMFF94) and semiempirical AM1 geometry optimizations, yielded results that are in fairly good agreement with the experimental observations.     

Palladium catalysis for the synthesis of hydrophobic C-6 and C-2 aryl 2'-deoxynucleosides. Comparison of C-C versus C-N bond formation as well as C-6 versus C-2 reactivity

Suzuki-Miyaura cross-coupling of haloaromatic compounds with arylboronic acids provides a simple entry to biaryl systems. Despite its ease, to date, there are no detailed investigations of this procedure for deoxynucleoside modification. As shown in this study, a wide variety of C-6 arylpurine 2'-deoxyriboside (C-6 aryl 2'-deoxynebularine analogues) and C-2 aryl 2'-deoxyinosine analogues can be conveniently prepared via the Pd-mediated cross-coupling of arylboronic acids with the C-6 halonucleosides, 6-bromo- or 6-chloro-9[2-deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-beta-D-erythro-pentofuranosyl]purine (1 and 2), and the C-2 halonucleoside, 2-bromo-O(6)-benzyl-3',5'-bis-O-(tert-butyldimethylsilyl)-2'-deoxyinosine (3). Although bromonucleoside 1 proved to be a good substrate for the Pd-catalyzed Suzuki-Miyaura cross-couplings, we have noted that for several C-6 arylations, the chloronucleoside 2 provides superior coupling yields. Also described in this study is a detailed evaluation of catalytic systems that led to optimal product recoveries. Finally, a comparison of the C-C and C-N bond-forming reactions of deoxynucleosides is also reported. On the basis of this comparison, we provide evidence that C-N bond formation at the C-6 position, leading to N-aryl 2'-deoxyadenosine analogues, is more sensitive to the ligand used, whereas C-C bond-forming reactions at the same position are not. In contrast to the ligand dependency exhibited in C-N bond formation at the C-6 position, comparable reactions at the C-2 position of purine deoxynucleosides proceed with less sensitivity to the ligand used.