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  • 1
    Language: English
    In: The Journal of organic chemistry, 20 January 2012, Vol.77(2), pp.815-24
    Description: Beginning with a known 3-oxabicyclo[3.1.0]hexane scaffold (I), the relocation of the fused cyclopropane ring bond and the shifting of the oxygen atom to an alternative location engendered a new 2-oxabicyclo[3.1.0]hexane template (II) that mimics more closely the tetrahydrofuran ring of conventional nucleosides. The synthesis of this new class of locked nucleosides involved a novel approach that required the isocyanate II (B = NCO) with a hydroxyl-protected scaffold as a pivotal intermediate that was obtained in 11 steps from a known dihydrofuran precursor. The completion of the nucleobases was successfully achieved by quenching the isocyanate with the lithium salts of the corresponding acrylic amides that led to the uracil and thymidine precursors in a single step. Ring closure of these intermediates led to the target, locked nucleosides. The anti-HIV activity of 29 (uridine analogue), 31 (thymidine analogue), and 34 (cytidine analogue) was explored in human osteosarcoma (HOS) cells or modified HOS cells (HOS-313) expressing the herpes simplex virus 1 thymidine kinase (HSV-1 TK). Only the cytidine analogue showed moderate activity in HOS-313 cells, which means that the compounds are not good substrates for the cellular kinases.
    Keywords: Pyrimidine Nucleosides -- Chemical Synthesis
    ISSN: 00223263
    E-ISSN: 1520-6904
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  • 2
    Language: English
    In: J. Am. Chem. Soc, 25 October 2012, Vol.134((25) ; 06, 2012)
    Description: Y-family DNA polymerases participate in replication stress and DNA damage tolerance mechanisms. The properties that allow these enzymes to copy past bulky adducts or distorted template DNA can result in a greater propensity for them to make mistakes. Of the four human Y-family members, human DNA polymerase iota (hpol{iota}) is the most error-prone. In the current study, we elucidate the molecular basis for improving the fidelity of hpol{iota} through use of the fixed-conformation nucleotide North-methanocarba-2{prime}-deoxyadenosine triphosphate (N-MC-dATP). Three crystal structures were solved of hpol{iota} in complex with DNA containing a template 2{prime}-deoxythymidine (dT) paired with an incoming dNTP or modified nucleotide triphosphate. The ternary complex of hpol{iota} inserting N-MC-dATP opposite dT reveals that the adenine ring is stabilized in the anti orientation about the pseudo-glycosyl torsion angle, which mimics precisely the mutagenic arrangement of dGTP:dT normally preferred by hpol{iota}. The stabilized anti conformation occurs without notable contacts from the protein but likely results from constraints imposed by the bicyclo[3.1.0]hexane scaffold of the modified nucleotide. Unmodified dATP and South-MC-dATP each adopt syn glycosyl orientations to form Hoogsteen base pairs with dT. The Hoogsteen orientation exhibits weaker base-stacking interactions and is less catalytically favorable than anti N-MC-dATP. Thus, N-MC-dATP corrects the error-prone nature of hpol{iota} by preventing the Hoogsteen base-pairing mode normally observed for hpol{iota}-catalyzed insertion of dATP opposite dT. These results provide a previously unrecognized means of altering the efficiency and the fidelity of a human translesion DNA polymerase.
    Keywords: Basic Biological Sciences ; General And Miscellaneous//Mathematics, Computing, And Information Science ; Adducts ; Adenines ; Crystal Structure ; DNA ; DNA Damages ; DNA Polymerases ; Efficiency ; Enzymes ; Nucleotides ; Orientation ; Proteins ; Tolerance ; Torsion ; Chemistry
    ISSN: 0002-7863
    E-ISSN: 1520-5126
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  • 3
    Language: English
    In: Biochemistry-US, 19 September 2013, Vol.51((13) ; 04, 2012)
    Description: Incorporation of a bicyclo[3.1.0]hexane scaffold into the nucleoside sugar was devised to lock the embedded cyclopentane ring in conformations that mimic the furanose North and South sugar puckers. To analyze the effects of North-methanocarba-2'-deoxythymidine (N-MCdT) on the B-form DNA, we crystallized d(CGCGAA[mcTmcT]CGCG) with two N-MCdTs. Instead of a duplex, the 12mer forms a tetraloop hairpin, whereby loop N-MCdTs adopt the C4'-exo pucker (NE; P = 50 degree ). Thus, the bicyclic framework does not limit the pucker to the anticipated C2'-exo range (NNW; P = -18 degree ).
    Keywords: Sugar ; DNA Structure ; Nucleosides ; DNA ; Scaffolds ; Conformation ; Cyclopentane ; Antisense, Nucleotide Analogs;
    ISSN: 00062960
    E-ISSN: 15204995
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  • 4
    Language: English
    In: Tetrahedron Letters, 20 November 2013, Vol.54(47), pp.6307-6309
    Description: The base-mediated cyclization of , -dimesylate derivatives of cyclic and acyclic amino alcohols provides a simple access to five- and six-member sultams: isothiazolidine-1,1-dioxides and thiazinane-1,1-dioxides respectively.
    Keywords: Cyclization ; Sultams ; Aminoalcohols ; Chemistry
    ISSN: 0040-4039
    E-ISSN: 1873-3581
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  • 5
    Language: English
    In: The Journal of organic chemistry, 19 November 2010, Vol.75(22), pp.7659-69
    Description: Two conformationally locked versions of l-deoxythreosyl phosphonate nucleosides (2 and 3) were synthesized to investigate the preference of HIV reverse transcriptase for a conformation displaying either a fully diaxial or fully diequatorial disposition of substituents. Synthesis of the enantiomeric 4-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-2-ol carbocyclic nucleoside precursors (diaxially disposed) proceeded straightforwardly from commercially available (1R,4S)-4-hydroxy-2-cyclopent-2-enyl-1-yl acetate employing a hydroxyl-directed Simmons-Smith cyclopropanation that culminated with a Mitsunobu coupling of the purine base. For the more complicated 1-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-3-ol carbocyclic nucleoside precursors (diequatorially disposed), the obligatory linear approach required the syntheses of key 1-aminobicyclo[3.1.0.]hexan-3-yl benzoate precursors that were assembled via the amide variant of the Kulinkovich reaction involving the intramolecular cyclopropanation of a substituted δ-vinylamide. Completion of the purine ring was achieved by conventional approaches but with much improved yields through the use of a microwave reactor. The syntheses of the phosphonates and the corresponding diphosphates were achieved by conventional means. None of the diphosphates, which were supposed to act as nucleoside triphosphate mimics, could compete with dATP even when present in a 10-fold excess.
    Keywords: Bridged Bicyclo Compounds -- Chemistry ; Nucleosides -- Chemical Synthesis ; Sugar Phosphates -- Chemical Synthesis
    ISSN: 00223263
    E-ISSN: 1520-6904
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  • 6
    Language: English
    In: Biochemistry-US, 07 March 2013, Vol.51((45) ; 11, 2012)
    Description: DNA polymerases select for the incorporation of deoxyribonucleotide triphosphates (dNTPs) using amino acid side-chains that act as a "steric-gate" to bar improper incorporation of rNTPs. An additional factor in the selection of nucleotide substrates resides in the preferred geometry for the furanose moiety of the incoming nucleotide triphosphate. We have probed the role of sugar geometry during nucleotide selection by model DNA polymerases from Sulfolobus solfataricus using fixed conformation nucleotide analogues. North-methanocarba-dATP (N-MC-dATP) locks the central ring into a RNA-type (C2'-exo, North) conformation near a C3'-endo pucker, and South-methanocarba-dATP (S-MC-dATP) locks the central ring system into a (C3'-exo, South) conformation near a C2'-endo pucker. Dpo4 preferentially inserts N-MC-dATP and in the crystal structure of Dpo4 in complex with N-MC-dAMP, the nucleotide analogue superimposes almost perfectly with Dpo4 bound to unmodified dATP. Biochemical assays indicate that the S. solfataricus B-family DNA polymerase Dpo1 can insert and extend from both N-MC-dATP and S-MC-dATP. In this respect, Dpo1 is unexpectedly more tolerant of substrate conformation than Dpo4. The crystal structure of Dpo4 bound to S-MC-dADP shows that poor incorporation of the Southern pucker by the Y-family polymerase results from a hydrogen bond between the 3'-OH group of the nucleotide analogue and the OH group of the steric gate residue, Tyr12, shifting the S-MC-dADP molecule away from the dNTP binding pocket and distorting the base pair at the primer-template junction. These results provide insights into substrate specificity of DNA polymerases, as well as molecular mechanisms that act as a barrier against insertion of rNTPs.
    Keywords: Chemistry ; Anatomy & Physiology;
    ISSN: 00062960
    E-ISSN: 15204995
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  • 7
    Language: English
    In: Bioorganic & Medicinal Chemistry, 15 July 2012, Vol.20(14), pp.4186-4193
    Description: Modified thrombin-binding aptamers (TBAs) carrying uridine (U), 2′-deoxy-2′-fluorouridine (FU) and -methanocarbathymidine (NT) residues in the loop regions were synthesized and analyzed by UV thermal denaturation experiments and CD spectroscopy. The replacement of thymidines in the TGT loop by U and FU results in an increased stability of the antiparallel quadruplex structure described for the TBA while the presence of NT residues in the same positions destabilizes the antiparallel structure. The substitution of the thymidines in the TT loops for U, FU and NT induce a destabilization of the antiparallel quadruplex, indicating the crucial role of these positions. NMR studies on TBAs modified with uridines at the TGT loop also confirm the presence of the antiparallel quadruplex structure. Nevertheless, replacement of two Ts in the TT loops by uridine gives a more complex scenario in which the antiparallel quadruplex structure is present along with other partially unfolded species or aggregates.
    Keywords: Quadruplex ; Thrombin-Binding Aptamer ; NMR ; Oligonucleotide Synthesis ; Uridine ; 2′-Deoxy-2′-Fluorouridine ; North-Methanocarbathymidine ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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  • 8
    Language: English
    In: Nature, November 2018, Vol.563(7732), pp.E27
    Description: We wish to correct two mutations in Supplementary Table 4 of this Letter. The NCI-H460 cell line was annotated as being mutant for TP53. NCI-H460 has been verified to be TP53 wild type by several sources. The NCI-H2009 cell line was annotated as being mutant for PIK3CA. As annotated by COSMIC (ref. 24 of the original Letter) and CCLE (ref. 25 of the original Letter), the NCI-H2009 cell line has a mutation in PIK3C3, rather than PIK3CA. The cell line is wild type for PIK3CA. The Supplementary Information of this Amendment contains the corrected Supplementary Table 4. These errors do not affect our conclusions. The original Letter has not been corrected.
    Keywords: Tumors ; Tumor Proteins;
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 9
    In: Nature, 2015
    Description: Non-small-cell lung cancer is the leading cause of cancer-related death worldwide (1). Chemotherapies such as the topoisomerase II (TopoII) inhibitor etoposide effectively reduce disease in a minority of patients with this cancer (2,3); therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention (4). A promising potential epigenetic target is the methyltransferase EZH2, which in the context of the polycomb repressive complex 2 (PRC2) is well known to tri-methylate histone H3 at lysine 27 (H3K27me3) and elicit gene silencing (5). Here we demonstrate that EZH2 inhibition has differential effects on the TopoII inhibitor response of non-small-cell lung cancers in vitro and in vivo. EGFR and BRG1mutations are genetic biomarkers that predict enhanced sensitivity to TopoII inhibitor in response to EZH2 inhibition. BRG1 loss-of-function mutant tumours respond to EZH2 inhibition with increased S phase, anaphase bridging, apoptosis and TopoII inhibitor sensitivity. Conversely, EGFR and BRG1 wild-type tumours upregulate BRG1in response to EZH2 inhibition and ultimately become more resistant to TopoII inhibitor. EGFR gain-of-function mutant tumours are also sensitive to dual EZH2 inhibition and TopoII inhibitor, because of genetic antagonism between EGFR and BRG1. These findings suggest an opportunity for precision medicine in the genetically complex disease of non-small-cell lung cancer.
    Keywords: Epidermal Growth Factor Receptors -- Health Aspects ; Non-Small Cell Lung Cancer -- Genetic Aspects ; Non-Small Cell Lung Cancer -- Drug Therapy ; Cancer Treatment -- Research ; Gene Expression -- Research ; Protein Research ; Cancer Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 2011, Vol.108(13), pp.5449-5454
    Description: Environmental factors interact with the genome throughout life to determine gene expression and, consequently, tissue function and disease risk. One such factor that is known to play an important role in determining long-term metabolic health is diet during critical periods of development. Epigenetic regulation of gene expression has been implicated in mediating these programming effects of early diet. The precise epigenetic mechanisms that underlie these effects remain largely unknown. Here, we show that the transcription factor Hnf4a, which has been implicated in the etiology of type 2 diabetes (T2D), is epigenetically regulated by maternal diet and aging in rat islets. Transcriptional activity of Hnf4a in islets is restricted to the distal P2 promoter through its open chromatin configuration and an islet-specific interaction between the P2 promoter and a downstream enhancer. Exposure to suboptimal nutrition during early development leads to epigenetic silencing at the enhancer region, which weakens the P2 promoter-enhancer interaction and results in a permanent reduction in Hnf4a expression. Aging leads to progressive epigenetic silencing of the entire Hnf4a locus in islets, an effect that is more pronounced in rats exposed to a poor maternal diet. Our findings provide evidence for environmentally induced epigenetic changes at the Hnf4a enhancer that alter its interaction with the P2 promoter, and consequently determine T2D risk. We therefore propose that environmentally induced changes in promoter-enhancer interactions represent a fundamental epigenetic mechanism by which nutrition and aging can influence long-term health. ; p. 5449-5454.
    Keywords: Environmental Factors ; Etiology ; Diet ; Islets Of Langerhans ; Genes ; Transcription Factors ; Loci ; Early Development ; Transcription (Genetics) ; Gene Expression Regulation ; Risk ; Maternal Nutrition ; Noninsulin-Dependent Diabetes Mellitus ; Epigenetics ; Gene Expression ; Rats ; Chromatin
    ISSN: 0027-8424
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