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31.
32.
Fluorescence Probes for ALKBH2 Allow the Measurement of DNA Alkylation Repair and Drug Resistance Responses 下载免费PDF全文
David L. Wilson Dr. Andrew A. Beharry Dr. Avinash Srivastava Prof. Dr. Timothy R. O'Connor Prof. Dr. Eric T. Kool 《Angewandte Chemie (International ed. in English)》2018,57(39):12896-12900
The DNA repair enzyme ALKBH2 is implicated in both tumorigenesis as well as resistance to chemotherapy in certain cancers. It is currently under study as a potential diagnostic marker and has been proposed as a therapeutic target. To date, however, there exist no direct methods for measuring the repair activity of ALKBH2 in vitro or in biological samples. Herein, we report a highly specific, fluorogenic probe design based on an oligonucleotide scaffold that reports directly on ALKBH2 activity both in vitro and in cell lysates. Importantly, the probe enables the monitoring of cellular regulation of ALKBH2 activity in response to treatment with the chemotherapy drug temozolomide through a simple fluorescence assay, which has only previously been observed through indirect means such as qPCR and western blots. Furthermore, the probe provides a viable high‐throughput assay for drug discovery. 相似文献
33.
Smietana M Johnson RB Wang QM Kool ET 《Chemistry (Weinheim an der Bergstrasse, Germany)》2004,10(1):173-181
A convergent strategy for the synthesis of cyclic nucleotide-hybrid molecules on controlled pore glass is reported. A major advantage of the approach is the lack of restrictions on the sequence and structural variation, allowing the incorporation of modified ribonucleosides (such as 2'-OMe-ribonucleotides), as well as threoninol derivatives. This methodology allows a fully automated assembly by means of standard phosphoramidite chemistry and is based on a recently published procedure for the preparation of cyclic oligodinucleotides in the DNA series (M. Smietana, E. T. Kool, Angew. Chem. 2002, 114, 3856-3859; Angew. Chem. Int. Ed. Engl. 2002, 41, 3704-3707). A library of potential cyclic hybrid inhibitor compounds targeting hepatitis C virus NS5B enzyme (the replicating polymerase of HCV) was generated by means of the parallel-pool strategy. Screening of the library revealed that cyclic hybrid c(C(OME)EthenodA) was a significant inhibitor of NS5B, with an IC(50) of 40 microM. Preliminary structure-activity studies of this lead compound are described. 相似文献
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James C. Delaney Dr. Jianmin Gao Dr. Haibo Liu Dr. Nidhi Shrivastav John M. Essigmann Prof. Dr. Eric T. Kool Prof. Dr. 《Angewandte Chemie (International ed. in English)》2009,48(25):4524-4527
Supersize me! Size‐expanded DNA bases (xDNA) are able to encode natural DNA sequences in replication. In vitro experiments with a DNA polymerase show nucleotide incorporation opposite the xDNA bases with correct pairing. In vivo experiments using E. coli show that two xDNA bases (xA and xC, see picture) encode the correct replication partners.
36.
Here we test the steric effects of added size on DNA base pairing and replication by the use of thiocarbonyl group replacements for natural nucleoside thymidine. The 2-thioT (2S) and 4-thioT (4S) nucleosides were reported previously, but their pairing specificity and replication fidelity were unknown. We find that 2S pairs with higher specificity than thymidine, and both 2S and 4S nucleoside triphosphates are replicated with higher efficiency than natural dTTP. The results indicate possible biotechnological uses for these analogues and have implications in the ongoing use of thionucleobases in cancer treatment. 相似文献
37.
A new design for DNA bases and base pairs is described in which the pyrimidine bases are widened by naphtho-homologation. Two naphtho-homologated deoxyribosides, dyyT (1) and dyyC (2), were synthesized and could be incorporated into oligonucleotides as suitably protected phosphoramidite derivatives. The deoxyribosides were found to be fluorescent, with emission maxima at 446 and 433 nm, respectively. Studies with single substitutions of 1 and 2 in the natural DNA context revealed exceptionally strong base stacking propensity for both. Sequences containing multiple substitutions of 1 and 2 paired opposite adenine and guanine were subsequently mixed and studied by several analytical methods. Data from UV mixing experiments, FRET measurements, fluorescence quenching experiments, and hybridizations on beads suggest that complementary "doublewide DNA" (yyDNA) strands may self-assemble into helical complexes with 1:1 stoichiometry. Data from thermal denaturation plots and CD spectra were less conclusive. Control experiments in one sequence context gave evidence that yyDNA helices, if formed, are preferentially antiparallel and are sequence selective. Hypothesized base pairing schemes are analogous to Watson-Crick pairing, but with glycosidic C1'-C1' distances widened by over 45%, to ca. 15.2 A. The possible self-assembly of the double-wide DNA helix establishes a new limit for the size of information-encoding, DNA-like molecules, and the fluorescence of yyDNA bases suggests uses as reporters in monomeric and oligomeric forms. 相似文献
38.
We report the synthesis and DNA incorporation of a novel C-5 thiopropyne-substituted thymidine derivative which can be used to bring about covalent crosslinks between two noncomplementary DNA strands. This modified thymine pairs normally with adenine in duplex DNA and is shown not to be destabilizing to DNA double helices. Placement of the thiol-nucleotide near the center of opposing pyrimidine strands in pyr·pur·pyr triple helices results in crosslinking of the pyrimidine strands under aerobic conditions. Thermal melting studies at neutral pH show that such crosslinked ligands bind complementary purine strands with higher affinity than is possible with simple Watson-Crick recognition alone. In addition, we describe the construction of a triplex-forming circular oligonucleotide which contains a similar disulfide link across the center. This macrobicyclic ligand binds with extremely high affinity and sequence selectivity to a complementary purine DNA strand. The formation of crosslinks across two noncomplementary strands represents a new strategy for increasing affinity and selectivity of DNA recognition. 相似文献
39.
[reaction: see text] An extremely simple and versatile method for placing an electrophilic functional group (iodide) at the 5' end of oligodeoxyribonucleotides is described. The reaction is carried out while the protected oligodeoxyribonucleotide remains on a solid support and utilizes inexpensive iodination chemistry. We demonstrate that this reaction can be automated on a DNA synthesizer as the last step of DNA synthesis. 相似文献
40.
Although the preparation of conjugates of oligonucleotides is by now commonplace, existing methods (usually utilizing thiols or primary amines) are generally expensive, and often require postsynthetic reaction with the DNA followed by a separate purification. Here we describe simple procedures for a broad set of direct 5'-end (5'-terminal carbon) functionalizations of DNA oligonucleotides while they remain on the synthesizer column. 5'-Iodinated oligonucleotides (prepared by an automated cycle as previously reported) are converted directly to 5'-azides, 5'-thiocarbamates, and alkyl and aryl 5'-thioethers in high yields. Further, we demonstrate high-yielding conversions of DNA-azides to 5'-amines, and of thiocarbamates to 5'-thiols. Finally, we report a new, one-pot conversion of naturally substituted 5'-OH oligonucleotides (again on the solid support) to 5'-amino-oligonucleotides. All of the above reactions are demonstrated in multiple sequence contexts. Most of the procedures are automatable. 相似文献