7-Deazaguanine modifications protect phage DNA from host restriction systems.

Genome modifications are central components of the continuous arms race between viruses and their hosts. The archaeosine base (G), which was thought to be found only in archaeal tRNAs, was recently detected in genomic DNA of Enterobacteria phage 9g and was proposed to protect phage DNA from a wide variety of restriction enzymes. In this study, we identify three additional 2'-deoxy-7-deazaguanine modifications, which are all intermediates of the same pathway, in viruses: 2'-deoxy-7-amido-7-deazaguanine (dADG), 2'-deoxy-7-cyano-7-deazaguanine (dPreQ) and 2'-deoxy-7- aminomethyl-7-deazaguanine (dPreQ).

Identification of the minimal bacterial 2'-deoxy-7-amido-7-deazaguanine synthesis machinery.

The 7-deazapurine derivatives, 2'-deoxy-7-cyano-7-deazaguanosine (dPreQ ) and 2'-deoxy-7-amido-7-deazaguanosine (dADG) are recently discovered DNA modifications encoded by the dpd cluster found in a diverse set of bacteria. Here we identify the genes required for the formation of dPreQ and dADG in DNA and propose a biosynthetic pathway. The preQ base is a precursor that in Salmonella Montevideo, is synthesized as an intermediate in the pathway of the tRNA modification queuosine.

Exploiting the Inherent Photophysical Properties of the Major Tirapazamine Metabolite in the Development of Profluorescent Substrates for Enzymes That Catalyze the Bioreductive Activation of Hypoxia-Selective Anticancer Prodrugs.

Hypoxia-selective cytotoxins (HSCs) seek to exploit the oxygen-poor nature of tumor tissue for therapeutic gain. Typically, HSCs require activation by one-electron bioreductive enzymes such as NADPH:cytochrome P450 reductase (CYPOR). Thus, successful clinical deployment of HSCs may be facilitated by the development and implementation of diagnostic probes that detect the presence of relevant bioreductive enzymes in tumor tissue.

Application of Suzuki-Miyaura and Buchwald-Hartwig Cross-coupling Reactions to the Preparation of Substituted 1,2,4-Benzotriazine 1-Oxides Related to the Antitumor Agent Tirapazamine.

Many 1,2,4-benzotriazine 1,4-dioxides display the ability to selectively kill the oxygen-poor cells found in solid tumors. As a result, there is a desire for synthetic routes that afford access to substituted 1,2,4-benzotriazine 1-oxides that can be used as direct precursors in the synthesis of 1,2,4-benzotriazine 1,4-dioxides. Here we describe the use of Suzuki-Miyaura and Buchwald-Hartwig cross-coupling reactions for the construction of various 1,2,4-benzotriazine 1-oxide analogs bearing substituents at the 3-, 6-, and 7-positions.

Covalent Allosteric Inactivation of Protein Tyrosine Phosphatase 1B (PTP1B) by an Inhibitor-Electrophile Conjugate.

Protein tyrosine phosphatase 1B (PTP1B) is a validated drug target, but it has proven difficult to develop medicinally useful, reversible inhibitors of this enzyme. Here we explored covalent strategies for the inactivation of PTP1B using a conjugate composed of an active site-directed 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxide inhibitor connected via a short linker to an electrophilic α-bromoacetamide moiety. Inhibitor-electrophile conjugate 5a caused time-dependent loss of PTP1B activity consistent with a covalent inactivation mechanism.

m(6)A-LAIC-seq reveals the census and complexity of the m(6)A epitranscriptome.

N(6)-Methyladenosine (m(6)A) is a widespread, reversible chemical modification of RNA molecules, implicated in many aspects of RNA metabolism. Little quantitative information exists as to either how many transcript copies of particular genes are m(6)A modified ('m(6)A levels') or the relationship of m(6)A modification(s) to alternative RNA isoforms. To deconvolute the m(6)A epitranscriptome, we developed m(6)A-level and isoform-characterization sequencing (m(6)A-LAIC-seq).

Novel genomic island modifies DNA with 7-deazaguanine derivatives.

The discovery of ∼20-kb gene clusters containing a family of paralogs of tRNA guanosine transglycosylase genes, called tgtA5, alongside 7-cyano-7-deazaguanine (preQ0) synthesis and DNA metabolism genes, led to the hypothesis that 7-deazaguanine derivatives are inserted in DNA. This was established by detecting 2'-deoxy-preQ0 and 2'-deoxy-7-amido-7-deazaguanosine in enzymatic hydrolysates of DNA extracted from the pathogenic, Gram-negative bacteria Salmonella enterica serovar Montevideo. These modifications were absent in the closely related S.

Crystal structure of methyl (S)-2-{(R)-4-[(tert-but-oxy-carbon-yl)amino]-3-oxo-1,2-thia-zolidin-2-yl}-3-methyl-butano-ate: a chemical model for oxidized protein tyrosine phosphatase 1B (PTP1B).

The asymmetric unit of the title compound, C14H24N2O5S, contains two independent mol-ecules (A and B). In each mol-ecule, the iso-thia-zolidin-3-one ring adopts an envelope conformation with the methyl-ene C atom as the flap. In the crystal, the A mol-ecules are linked to one another by N-H⋯O hydrogen bonds, forming columns along [010].

Crystal structure of 5-{4'-[(2-{2-[2-(2-ammonio-eth-oxy)eth-oxy]eth-oxy}eth-yl)carbamo-yl]-4-meth-oxy-[1,1'-biphen-yl]-3-yl}-3-oxo-1,2,5-thia-diazo-lidin-2-ide 1,1-dioxide: a potential inhibitor of the enzyme protein tyrosine phosphatase 1B (PTP1B).

The title compound, C24H32N4O8S, (I), crystallizes as a zwitterion. The terminal amine N atom of the [(2-{2-[2-(2-ammonio-eth-oxy)eth-oxy]eth-oxy}eth-yl)carbamo-yl] side chain is protonated, while the 1,2,5-thia-diazo-lidin-3-one 1,1-dioxide N atom is deprotonated. The side chain is turned over on itself with an intra-molecular N-H⋯O hydrogen bond.

Near-silence of isothiocyanate carbon in (13)C NMR spectra: a case study of allyl isothiocyanate.

(1)H and (13)C NMR spectra of allyl isothiocyanate (AITC) were measured, and the exchange dynamics were studied to explain the near-silence of the ITC carbon in (13)C NMR spectra. The dihedral angles α = ∠(C1-C2-C3-N4) and β = ∠(C2-C3-N4-C5) describe the conformational dynamics (conformation change), and the bond angles γ = ∠(C3-N4-C5) and ε = ∠(N4-C5-S6) dominate the molecular dynamics (conformer flexibility). The conformation space of AITC contains three minima, Cs-M1 and enantiomers M2 and M2'; the exchange between conformers is very fast, and conformational effects on (13)C chemical shifts are small (νM1 - νM2 < 3 ppm).

Crystal structure of N-(quinolin-6-yl)hydroxyl-amine.

The title compound, C9H8N2O, crystallized with four independent mol-ecules in the asymmetric unit. The four mol-ecules are linked via one O-H⋯N and two N-H⋯N hydrogen bonds, forming a tetra-mer-like unit. In the crystal, mol-ecules are further linked by O-H⋯N and N-H⋯O hydrogen bonds forming layers parallel to (001).