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1.
Phys Chem Chem Phys ; 23(34): 19043-19053, 2021 Sep 14.
Article En | MEDLINE | ID: mdl-34612442

Reaction pathway of prebiotic reactions for formation of the pteridines: pterin, xanthopterine, isoxanthopterine and leucopterine, as well as the purine nucleobase guanine from pure formamide are presented. In these reactions, formamide or its tautomer, formimidic acid, play the role of proton-carrying catalyst. All required raw materials, such as hydrogen cyanide, ammonia, water, formic acid, urea, 2-aminomalononitrile, glyoxal, glyoxylic acid and oxalic acid needed in the self-catalyzed reactions are obtained by partial decomposition of formamide. We show that the prebiotic formation of nucleobases and pterins is closely linked and they probably coexisted at the beginning of chemical evolution.


Formamides/chemistry , Guanine/chemical synthesis , Prebiotics , Pterins/chemical synthesis , Catalysis , Density Functional Theory , Evolution, Chemical , Guanine/chemistry , Pterins/chemistry , Temperature
2.
Article En | MEDLINE | ID: mdl-32312162

АBSTRACTEsters of the antiherpetic drugs ganciclovir, penciclovir with the bile acids (cholic, chenodeoxycholic and deoxycholic) and amino acid esters of acyclovir were generated and evaluated for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The antiviral assays demonstrated that modified analogs of ACV and PCV are less active compared to the initial substances against HSV-1and HSV-2. CC50 for ganciclovir-deoxycholate corresponded to the CC50 of the other analogs and its activity is lower than ganciclovir. Obtained results show that tested modification do not improve bioavailability of nucleoside analogs in cells.


Acyclovir/pharmacology , Antiviral Agents/pharmacology , Ganciclovir/pharmacology , Guanine/pharmacology , Herpesvirus 1, Human/drug effects , Herpesvirus 2, Human/drug effects , Acyclovir/chemical synthesis , Acyclovir/chemistry , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cattle , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Ganciclovir/chemical synthesis , Ganciclovir/chemistry , Guanine/chemical synthesis , Guanine/chemistry , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship
3.
Molecules ; 25(4)2020 Feb 12.
Article En | MEDLINE | ID: mdl-32059504

The synthesis of an unreported 2-aminopyrrolidine-1-carboxamidine unit is here described for the first time. This unusual and promising structure was attained through the oxidative decarboxylation of amino acids using the pair of reagents, silver(I)/peroxydisulfate (Ag(I)/S2O82-) followed by intermolecular (in the case of l-proline derivative) and intramolecular trapping (in the case of acyl l-arginine) by N-nucleophiles. The l-proline approach has a broader scope for the synthesis of 2-aminopyrrolidine-1-carboxamidine derivatives, whereas the intramolecular cyclization afforded by the l-acylarginines, when applied, results in higher yields. The former allowed the first synthesis of cernumidine, a natural alkaloid isolated in 2011 from Solanum cernuum Vell, as its racemic form.


Guanine/chemical synthesis , Molecular Structure , Pyrrolidines/chemical synthesis , Alkaloids/chemical synthesis , Alkaloids/chemistry , Amines/chemistry , Cyclization , Decarboxylation , Guanine/chemistry , Oxidation-Reduction , Pyrrolidines/chemistry , Silver/chemistry
4.
Article En | MEDLINE | ID: mdl-31588835

Synthesis of exclusive N2-(isobutyryl)-9-(carboxymethyl)guanine, an important moiety for peptide nucleic acid synthesis has been reported through a high-yielding reaction scheme starting from 6-chloro-2-amino purine. Crystal structures of two intermediates confirmed the formation of N9-regioisomer. This new synthetic route can potentially replace the conventional tedious method with moderate overall yield.


Guanine/chemical synthesis , Peptide Nucleic Acids/chemical synthesis , Crystallography, X-Ray , Guanine/analogs & derivatives , Guanine/chemistry , Models, Molecular , Molecular Structure , Peptide Nucleic Acids/chemistry
5.
Bioorg Med Chem Lett ; 29(11): 1320-1324, 2019 06 01.
Article En | MEDLINE | ID: mdl-30956013

RNA higher-order structures play an important role for control of the gene expression, and the small molecules binding to these structures have potential to act as interfering agents in the RNA-mediated-pathway. In this study, we synthesized new RNA binding molecules based on the G-clamp structure and evaluated their binding properties using the model RNA. The monomeric G-clamp ligand exhibited a fluorescence quenching with RNA-binding. The dimeric G-clamp ligand showed a significant fluorescence OFF/ON response to the RNA hairpin structure containing the guanines, indicating a high affinity of the G-clamp dimer to two neighboring guanines located in the RNA hairpin loop.


Guanine/chemistry , RNA/chemistry , Binding Sites , Dose-Response Relationship, Drug , Fluorescence , Guanine/chemical synthesis , Ligands , Molecular Structure , Structure-Activity Relationship
6.
Molecules ; 24(8)2019 Apr 12.
Article En | MEDLINE | ID: mdl-31013786

Purine isosteres present excellent opportunities in drug design and development. Using isosteres of natural purines as scaffolds for the construction of new therapeutic agents has been a valid strategy of medicinal chemistry. Inspired by the similarity to isoguanine, we attempted to develop a practical method for the preparation of 5-aza-isoguanines. Several synthetic approaches were explored to establish a robust general protocol for the preparation of these compounds. The significant difference in the reactivity of the C-5 and C-7 electrophilic centers of 1,2,4-triazolo[1,5-a][1,3,5]triazines (5-azapurines) towards nucleophiles was demonstrated. The most practical and general method for the preparation of 5-aza-isoguanines involved a regioselective reaction of ethoxycarbonyl isothiocyanate with a 5-aminotriazole. The intramolecular ring closure of the resulted product followed by the S-methylation afforded 7-methylthio-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-one, which could be effectively aminated with various amines. The resulted 5-aza-isoguanines resemble a known purine nucleoside phosphorylase inhibitor and could be interesting for further investigations as potential anticancer agents.


Antineoplastic Agents , Enzyme Inhibitors , Guanine , Purine Nucleosides , Purine-Nucleoside Phosphorylase/antagonists & inhibitors , Triazines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Guanine/chemical synthesis , Guanine/chemistry , Purine Nucleosides/chemical synthesis , Purine Nucleosides/chemistry
7.
Bioorg Med Chem ; 27(6): 1023-1033, 2019 03 15.
Article En | MEDLINE | ID: mdl-30738653

A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against herpes simplex virus 1 and 2 (HSV-1, HSV-2) and thymidine kinase deficient (ACV resistant) HSV-1. The tricyclic HBG derivatives were devoid of inhibitory activity however several of the tricyclic PCV derivatives showed promising antiviral activity, in particular 9g (R = 4-MeO-C6H4) displayed good inhibitory activity (HSV-1 EC50 1.5 µM, HSV-2 EC50 0.8 µM) and retained inhibitory activity in HSV-1 TK- cells (EC50 0.8 µM). Computational docking experiments supported the biological data observed and this preliminary study provides useful data for further development of tricyclic acyclic nucleoside derivatives with improved lipophilicity and retention of activity in HSV-1 TK deficient strains. Also, the new tricyclic derivatives were evaluated against a broad range of other DNA and RNA viruses, but were found to be inactive at subtoxic concentrations. In addition, weak to moderate cytostatic effect was observed for the new compounds.


Acyclovir/analogs & derivatives , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Herpesvirus 1, Human/drug effects , Herpesvirus 2, Human/drug effects , Acyclovir/chemical synthesis , Acyclovir/chemistry , Acyclovir/pharmacology , Antiviral Agents/chemical synthesis , Guanine/analogs & derivatives , Guanine/chemical synthesis , Guanine/pharmacology , Herpes Genitalis/drug therapy , Herpes Simplex/drug therapy , Humans , Models, Molecular
8.
J Pharm Sci ; 107(11): 2927-2937, 2018 11.
Article En | MEDLINE | ID: mdl-29960026

(2S,3S)-1,2:3,4-diepoxybutane (DEB) cross-links DNA guanines by forming the intermediate epoxy-adduct ((2'S,3'S)-N-7-(3',4'-epoxy-2'-hydroxybut-1'-yl)guanine [EHBG]). This process is presently considered a primary mechanism for the action of treosulfan (TREO), the prodrug that transforms to DEB via the monoepoxide intermediate (2S,3S)-1,2-epoxybutane-3,4-diol 4-methanesulfonate (EBDM). In this article, the N-7-guanine adduct of EBDM ((2'S,3'S)-N-7-(2'3'-dihydroxy-4'-methylsulfonyloxybut-1'-yl)guanine [HMSBG]) was synthesized for the first time, and its stability was investigated at physiological in vitro conditions. To synthesize HMSBG, EBDM, formed in-situ from TREO, was treated with guanosine in glacial acetic acid at 60°C followed by ribose cleavage in 1 M HCl at 80°C. HMSBG was stable during the synthesis, which showed that a ß-hydroxy group protects the sulfonate moiety against hydrolysis in acid environment. At pH 7.2 and 37°C, HMSBG exclusively underwent first-order epoxidation to EHBG with a half-life of 5.0 h. EHBG further decomposed to trihydroxybutyl-guanine, chlorodihydroxybutyl-guanine (major products), phosphodihydroxy-guanine, and a structural isomer (minor products). The isomeric derivative was identified as guanine with a fused 7-membered ring, which provided a new insight into the EHBG stability. To conclude, the exclusive conversion of HMSBG to EHBG indicates that EBDM might contribute to DNA cross-linking independently from DEB and play a more important role in the TREO action than expected before.


Antineoplastic Agents, Alkylating/chemistry , Busulfan/analogs & derivatives , Guanine/analogs & derivatives , Intercalating Agents/chemistry , Prodrugs/chemistry , Antineoplastic Agents, Alkylating/chemical synthesis , Busulfan/chemical synthesis , Busulfan/chemistry , Chromatography, High Pressure Liquid , Drug Stability , Guanine/chemical synthesis , Hydrogen-Ion Concentration , Hydrolysis , Intercalating Agents/chemical synthesis , Kinetics , Magnetic Resonance Spectroscopy , Prodrugs/chemical synthesis
9.
J Am Chem Soc ; 140(20): 6391-6399, 2018 05 23.
Article En | MEDLINE | ID: mdl-29723476

This paper describes the synthesis of giant cyclic molecules having diameters of 10-20 nm. The molecules are prepared through the reactions of a fusion protein building block with small molecule linkers that are terminated in irreversible inhibitors of enzyme domains present in the fusion. This building block has N-terminal cutinase and C-terminal SnapTag domains that react irreversibly with p-nitrophenyl phosphonate (pNPP) and benzylguanine (BG) groups, respectively. We use a bis-BG and a BG-pNPP linker to join these fusion proteins into linear structures that can then react with a bis-pNPP linker that joins the ends into a cyclic product. The last step can occur intramolecularly, to give the macrocycle, or intermolecularly with another equivalent of linker, to give a linear product. Because these are coupled first- and second-order processes, an analysis of product yields from reactions performed at a range of linker concentrations gives rate constants for cyclization. We determined these to be 9.7 × 10-3 s-1, 2.3 × 10-3 s-1, and 8.1 × 10-4 s-1 for the dimer, tetramer, and hexamer, respectively. This work demonstrates an efficient route to cyclic macromolecules having nanoscale dimensions and provides new scaffolds that can be generated using the megamolecule approach.


Carboxylic Ester Hydrolases/chemistry , Guanine/analogs & derivatives , Macrocyclic Compounds/chemistry , Nitrophenols/chemistry , O(6)-Methylguanine-DNA Methyltransferase/chemistry , Organophosphonates/chemistry , Carboxylic Ester Hydrolases/chemical synthesis , Cross-Linking Reagents/chemical synthesis , Cross-Linking Reagents/chemistry , Cyclization , Guanine/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Models, Molecular , Nitrophenols/chemical synthesis , O(6)-Methylguanine-DNA Methyltransferase/chemical synthesis , Organophosphonates/chemical synthesis , Protein Domains , Protein Multimerization
10.
PLoS One ; 12(9): e0184630, 2017.
Article En | MEDLINE | ID: mdl-28926581

INTRODUCTION: Cell transplantation is an innovative therapeutic approach after brain injury to compensate for tissue damage. To have real-time longitudinal monitoring of intracerebrally grafted cells, we explored the feasibility of a molecular imaging approach using thymidine kinase HSV1-TK gene encoding and [18F]FHBG as a reporter probe to image enzyme expression. METHODS: A stable neuronal cell line expressing HSV1-TK was developed with an optimised mammalian expression vector to ensure long-term transgene expression. After [18F]FHBG incubation under defined parameters, calibration ranges from 1 X 104 to 3 X 106 Neuro2A-TK cells were analysed by gamma counter or by PET-camera. In parallel, grafting with different quantities of [18F]FHBG prelabelled Neuro2A-TK cells was carried out in a rat brain injury model induced by stereotaxic injection of malonate toxin. Image acquisition of the rats was then performed with PET/CT camera to study the [18F]FHBG signal of transplanted cells in vivo. RESULTS: Under the optimised incubation conditions, [18F]FHBG cell uptake rate was around 2.52%. In-vitro calibration range analysis shows a clear linear correlation between the number of cells and the signal intensity. The PET signal emitted into rat brain correlated well with the number of cells injected and the number of surviving grafted cells was recorded via the in-vitro calibration range. PET/CT acquisitions also allowed validation of the stereotaxic injection procedure. Technique sensitivity was evaluated under 5 X 104 grafted cells in vivo. No [18F]FHBG or [18F]metabolite release was observed showing a stable cell uptake even 2 h post-graft. CONCLUSION: The development of this kind of approach will allow grafting to be controlled and ensure longitudinal follow-up of cell viability and biodistribution after intracerebral injection.


Brain Injuries/diagnostic imaging , Genetic Vectors/metabolism , Herpesvirus 1, Human/genetics , Positron Emission Tomography Computed Tomography , Radiopharmaceuticals/metabolism , Thymidine Kinase/genetics , Animals , Brain/diagnostic imaging , Brain Injuries/pathology , Cell Line , Cell Transplantation , Disease Models, Animal , Fluorine Radioisotopes/chemistry , Genetic Vectors/genetics , Guanine/analogs & derivatives , Guanine/chemical synthesis , Guanine/metabolism , Humans , Mice , Radiopharmaceuticals/chemical synthesis , Rats , Rats, Sprague-Dawley , Thymidine Kinase/metabolism
11.
Molecules ; 22(7)2017 Jul 12.
Article En | MEDLINE | ID: mdl-28704950

A series of acyclic selenopurine nucleosides 3a-f and 4a-g were synthesized based on the bioisosteric rationale between oxygen and selenium, and then evaluated for antiviral activity. Among the compounds tested, seleno-acyclovir (4a) exhibited the most potent anti-herpes simplex virus (HSV)-1 (EC50 = 1.47 µM) and HSV-2 (EC50 = 6.34 µM) activities without cytotoxicity up to 100 µM, while 2,6-diaminopurine derivatives 4e-g exhibited significant anti-human cytomegalovirus (HCMV) activity, which is slightly more potent than the guanine derivative 4d, indicating that they might act as prodrugs of seleno-ganciclovir (4d).


Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , Organoselenium Compounds/chemical synthesis , Purines/chemical synthesis , 2-Aminopurine/analogs & derivatives , 2-Aminopurine/chemical synthesis , 2-Aminopurine/pharmacology , Acyclovir/analogs & derivatives , Acyclovir/chemical synthesis , Acyclovir/pharmacology , Antiviral Agents/pharmacology , Cytomegalovirus/drug effects , Guanine/analogs & derivatives , Guanine/chemical synthesis , Guanine/pharmacology , Herpesvirus 1, Human/drug effects , Herpesvirus 2, Human/drug effects , Humans , Nucleosides/pharmacology , Organoselenium Compounds/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Purines/pharmacology , Simplexvirus/drug effects , Structure-Activity Relationship
12.
Nucleosides Nucleotides Nucleic Acids ; 36(7): 463-473, 2017 Jul 03.
Article En | MEDLINE | ID: mdl-28574799

Synthesis of a novel 2'-deoxy-guanine carbocyclic nucleoside 4 constructed with spiro[2.4]heptane core structure in the aglycon moiety was carried out. Radical-mediated 5-exo-dig mode cyclization and following cyclopropanation proceeded efficiently to furnish the spiro alcohol 10. Subsequent Mitsunobu-type glycosylation between 13 and 14, deoxygenation of the 2'-hydroxyl group of 16 and deprotection of 17 gave the title compound 4. Compound 4 demonstrated moderate anti-HBV activity (EC50 value of 0.12 ± 0.02 µM) and no cytotoxicity against HepG2 cells was observed up to 100 µM.


Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Guanine/analogs & derivatives , Hepatitis B virus/drug effects , Heptanes/chemistry , Antiviral Agents/chemical synthesis , Chemistry Techniques, Synthetic , Guanine/chemical synthesis , Guanine/chemistry , Guanine/pharmacology , Structure-Activity Relationship
13.
Biochemistry ; 56(13): 1841-1853, 2017 04 04.
Article En | MEDLINE | ID: mdl-28290677

DNA can be damaged by many compounds in our environment, and the resulting damaged DNA is commonly replicated by translesion synthesis (TLS) polymerases. Because the mechanism and efficiency of TLS are affected by the type of DNA damage, obtaining information for a variety of DNA adducts is critical. However, there is no structural information for the insertion of a dNTP opposite an O6-dG adduct, which is a particularly harmful class of DNA lesions. We used molecular dynamics (MD) simulations to investigate structural and energetic parameters that dictate preferred dNTP insertion opposite O6-benzyl-guanine (Bz-dG) by DNA polymerase IV, a prototypical TLS polymerase. Specifically, MD simulations were completed on all possible ternary insertion complexes and ternary -1 base deletion complexes with different Bz-dG conformations. Our data suggests that the purines are unlikely to be inserted opposite anti- or syn-Bz-dG, and dTTP is unlikely to be inserted opposite syn-Bz-dG, because of changes in the active site conformation, including critical hydrogen-bonding interactions and/or reaction-ready parameters compared to natural dG replication. In contrast, a preserved active site conformation suggests that dCTP can be inserted opposite either anti- or syn-Bz-dG and dTTP can be inserted opposite anti-Bz-dG. This is the first structural explanation for the experimentally observed preferential insertion of dCTP and misincorporation of dTTP opposite Bz-dG. Furthermore, we provide atomic level insight into why Bz-dG replication does not lead to deletion mutations, which is in contrast with the replication outcomes of other adducts. These findings provide a basis for understanding the replication of related O6-dG adducts.


Benzyl Compounds/chemical synthesis , DNA Adducts/chemistry , DNA Polymerase beta/chemistry , DNA Repair , DNA Replication , Deoxyguanine Nucleotides/chemistry , Escherichia coli Proteins/chemistry , Guanine/chemical synthesis , Catalytic Domain , DNA Damage , DNA Polymerase beta/genetics , DNA Polymerase beta/metabolism , Deoxyadenine Nucleotides/chemistry , Deoxyadenine Nucleotides/metabolism , Deoxycytosine Nucleotides/chemistry , Deoxycytosine Nucleotides/metabolism , Deoxyguanine Nucleotides/metabolism , Escherichia coli/chemistry , Escherichia coli/enzymology , Escherichia coli/genetics , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Guanine/analogs & derivatives , Hydrogen Bonding , Molecular Dynamics Simulation , Mutagenesis , Protein Structure, Secondary , Protein Structure, Tertiary , Thymine Nucleotides/chemistry , Thymine Nucleotides/metabolism
14.
J Med Chem ; 59(23): 10470-10478, 2016 12 08.
Article En | MEDLINE | ID: mdl-27933957

Human papillomavirus (HPV) high-risk genotypes such as HPV-16 and HPV-18 cause the majority of anogenital tract carcinomas, including cervical cancer, the second most common malignancy in women worldwide. Currently there are no approved antiviral agents that reduce or eliminate HPV and reverse virus-associated pathology. We synthesized and evaluated several alkoxyalkyl acyclic nucleoside phosphonate diesters and identified octadecyloxyethyl benzyl 9-[(2-phosphonomethoxy)ethyl]guanine (ODE-Bn-PMEG) as an active compound which strongly inhibited transient amplification of HPV-11, -16, and -18 origin-containing plasmid DNA in transfected cells at concentrations well below its cytotoxic concentrations. ODE-Bn-PMEG demonstrated increased uptake in human foreskin fibroblast cells and was readily converted in vitro to the active antiviral metabolite, PMEG diphosphate. The P-chiral enantiomers of ODE-Bn-PMEG were obtained and appeared to have equivalent antiviral activities against HPV. ODE-Bn-PMEG is a promising candidate for the local treatment of HPV-16 and HPV-18 and other high-risk types, an important unmet medical need.


Antiviral Agents/pharmacology , DNA, Viral/drug effects , Guanine/analogs & derivatives , Nucleic Acid Amplification Techniques , Organophosphonates/pharmacology , Papillomaviridae/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line, Tumor , Dose-Response Relationship, Drug , Guanine/chemical synthesis , Guanine/chemistry , Guanine/pharmacology , HEK293 Cells , HIV/drug effects , Herpesvirus 2, Human/drug effects , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Molecular Structure , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Papillomaviridae/genetics , Structure-Activity Relationship , Virus Replication/drug effects
15.
Sci Rep ; 6: 24499, 2016 Apr 19.
Article En | MEDLINE | ID: mdl-27091631

Electrochemical device with components having direct significance to biological life processes is a potent futuristic strategy for the realization of all-round green and sustainable development. We present here synthesis design, structural analysis and ion transport of a novel solid organic electrolyte (G7Li), a compound reminiscent of ion channels, derived from regioisomeric N7-guanine-carboxylate conjugate and Li-ions. G7Li, with it's in-built supply of Li(+)-ions, exhibited remarkably high lithium-ion transference number (= 0.75) and tunable room temperature ionic conductivity spanning three decades (≈10(-7) to 10(-3) Ω(-1) cm(-1)) as a function of moisture content. The ionic conductivity show a distinct reversible transition around 80-100 °C, from a dual Li(+) and H(+) (<100 °C) to a pure Li(+) conductor (>100 °C). Systematic studies reveal a transition from water-assisted Li-ion transport to Li hopping-like mechanism involving guanine-Li coordination. While as-synthesized G7Li has potential in humidity sensors, the anhydrous G7Li is attractive for rechargeable batteries.


Electrolytes/chemistry , Guanine/chemistry , Lithium/chemistry , Electric Conductivity , Electrolytes/chemical synthesis , Guanine/analogs & derivatives , Guanine/chemical synthesis , Ion Channels/chemistry , Ion Transport , Ions/chemistry , Water/chemistry
16.
J Org Chem ; 81(7): 2827-36, 2016 Apr 01.
Article En | MEDLINE | ID: mdl-27009432

A method for the diastereoselective synthesis of 6″-(Z)- and 6″-(E)-fluorinated analogues of the anti-HBV agent entecavir has been developed. Construction of the methylenecyclopentane skeleton of the target molecules has been accomplished by radical-mediated 5-exo-dig cyclization of the selenides 6 and 15 having the phenylsulfanylethynyl structure as a radical accepting moiety. In the radical reaction of the TBS-protected precursor 6, (Z)-anti-12 was formed as a major product. On the other hand, TIPS-protected 15 gave (E)-anti-12. The sulfur-extrusive stannylation of anti-12 furnished a mixture of geometric isomers of the respective vinylstannane, whereas benzoyl-protected 17 underwent the stannylation in the manner of retention of configuration. Following XeF2-mediated fluorination, introduction of the purine base and deoxygenation of the resulting carbocyclic guanosine gave the target (E)- and (Z)-3 after deprotection. Evaluation of the anti-HBV activity of 3 revealed that fluorine-substitution at the 6″-position of entecavir gave rise to a reduction in the cytotoxicity in HepG2 cells with retention of the antiviral activity.


Antiviral Agents/chemical synthesis , Guanine/analogs & derivatives , Guanosine/chemistry , HIV-1/drug effects , Hep G2 Cells/chemistry , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Guanine/chemical synthesis , Guanine/chemistry , Guanine/pharmacology , Hepatitis B virus/drug effects , Humans , Stereoisomerism , Structure-Activity Relationship
17.
Bioorg Med Chem ; 24(2): 226-31, 2016 Jan 15.
Article En | MEDLINE | ID: mdl-26712096

A novel potent xanthine oxidase inhibitor, 3-nitrobenzoyl 9-deazaguanine (LSPN451), was selected from a series of 10 synthetic derivatives. The enzymatic assays were carried out using an on-flow bidimensional liquid chromatography (2D LC) system, which allowed the screening¸ the measurement of the kinetic inhibition constant and the characterization of the inhibition mode. This compound showed a non-competitive inhibition mechanism with more affinity for the enzyme-substrate complex than for the free enzyme, and inhibition constant of 55.1±9.80 nM, about thirty times more potent than allopurinol. Further details of synthesis and enzymatic studies are presented herein.


Benzyl Compounds/pharmacology , Enzyme Inhibitors/pharmacology , Guanine/analogs & derivatives , Xanthine Oxidase/antagonists & inhibitors , Animals , Benzyl Compounds/chemical synthesis , Benzyl Compounds/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Guanine/chemical synthesis , Guanine/chemistry , Guanine/pharmacology , Humans , Molecular Structure , Purine-Nucleoside Phosphorylase/antagonists & inhibitors , Purine-Nucleoside Phosphorylase/metabolism , Schistosoma mansoni/enzymology , Structure-Activity Relationship , Xanthine Oxidase/metabolism
18.
Article En | MEDLINE | ID: mdl-26398890

A first microwave-assisted synthesis of a new class of novel purine thioglycoside analogues from readily available starting materials has been described. The key step of this protocol is the formation of sodium pyrazolo[1,5-a][1,3,5]triazine-4-thiolates via condensation of 5-amino-1H-pyrazoles with sodium cyanocarbonimidodithioate salt under microwave irradiation, followed by coupling with halo sugars to give the corresponding purine thioglycoside analogues. Further studies on the application of this method for the synthesis of other highly functionalized biologically active glycosides are underway.


Purine Nucleosides/chemical synthesis , Purines/chemical synthesis , Thioglycosides/chemical synthesis , Guanine/chemical synthesis , Guanine/chemistry , Microwaves , Purine Nucleosides/chemistry , Purines/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Thioglycosides/chemistry , Triazines/chemical synthesis , Triazines/chemistry
19.
Future Med Chem ; 7(13): 1809-28, 2015.
Article En | MEDLINE | ID: mdl-26416300

Nucleoside analogs are extremely useful for the development of therapeutic agents to control viral diseases and cancer. Among the numerous modifications on the nucleoside skeleton, replacement of the oxygen of the furanose ring by a CH2 group resulted in increased flexibility and higher resistance to phosphorylases and led to carbocyclic nucleoside analogs (or carbanucleosides). The broad spectrum of biological activities of carbocyclic nucleosides led to tremendous research interest in their syntheses. The article documents recent strategies for the synthesis of active carbocyclic nucleosides by presenting individual case studies, such as the neplanocins, entecavir and selected fluorinated carbocyclic nucleosides. Furthermore, it provides new insights into new directions for more potent and active carbocyclic nucleoside analogs.


Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Nucleosides/chemistry , Nucleosides/pharmacology , Virus Diseases/drug therapy , Viruses/drug effects , Adenosine/analogs & derivatives , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiviral Agents/chemical synthesis , Drug Discovery , Guanine/analogs & derivatives , Guanine/chemical synthesis , Guanine/chemistry , Guanine/pharmacology , Halogenation , Humans , Neoplasms/drug therapy , Nucleosides/chemical synthesis
20.
Molecules ; 20(9): 15944-65, 2015 Sep 02.
Article En | MEDLINE | ID: mdl-26364627

The human 8-oxoguanine DNA glycosylase OGG1 is involved in base excision repair (BER), one of several DNA repair mechanisms that may counteract the effects of chemo- and radiation therapy for the treatment of cancer. We envisage that potent inhibitors of OGG1 may be found among the 9-alkyl-8-oxoguanines. Thus we explored synthetic routes to 8-oxoguanines and examined these as OGG1 inhibitors. The best reaction sequence started from 6-chloroguanine and involved N-9 alkylation, C-8 bromination, and finally simultaneous hydrolysis of both halides. Bromination before N-alkylation should only be considered when the N-substituent is not compatible with bromination conditions. The 8-oxoguanines were found to be weak inhibitors of OGG1. 6-Chloro-8-oxopurines, byproducts in the hydrolysis of 2,6-halopurines, turned out to be slightly better inhibitors than the corresponding 8-oxoguanines.


DNA Glycosylases/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Guanine/analogs & derivatives , Alkylation , DNA Glycosylases/antagonists & inhibitors , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Guanine/chemical synthesis , Guanine/chemistry , Guanine/pharmacology , Humans , Substrate Specificity
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