Synthesis of Chromeno[2,3‑<i>d</i>]imidazol-9(1<i>H</i>)‑ones via Tandem Reactions of 3‑Iodochromones with Amidines Involving Copper-Catalyzed C–H Functionalization and C–O Bond Formation

A novel six-membered heterocyclic skeleton of imidazochromone was prepared via an efficient one-pot reaction including a key step of copper-catalyzed aerobic C–H intramolecular cycloetherification. Notably, this process does not require the presence of strong para electron-withdrawing groups on the phenol component. Also, the results of this effort show that acyl phenols containing electron-rich heterocycles participate in an efficient C–H activation/C–O formation process

The importance of fitting in: conformational preference of selenium 2′ modifications in nucleosides and helical structures

<div><p>Selenomethionine incorporation has proven useful in X-ray crystallography of proteins to obtain phase information. In nucleic acids, the introduction of selenium to different positions is beneficial for solving the phase problem as well, but its addition to the 2′ position also significantly enhances the crystal formation. The selenium modification in a single nucleotide shows a preference towards 2′-endo sugar puckering, which is in conflict with existing crystal structures where the duplex incorporated 2′-selenium-modified nucleotide is exclusively found in a 3′-endo conformation. Our work provides a rationale why 2′-selenium modifications facilitate crystallization despite this contradictory behavior.</p></div

Crystal Structure Studies of RNA Duplexes Containing s²U:A and s²U:U Base Pairs

Structural studies of modified nucleobases in RNA duplexes are critical for developing a full understanding of the stability and specificity of RNA base pairing. 2-Thio-uridine (s²U) is a modified nucleobase found in certain tRNAs. Thermodynamic studies have evaluated the effects of s²U on base pairing in RNA, where it has been shown to stabilize U:A pairs and destabilize U:G wobble pairs. Surprisingly, no high-resolution crystal structures of s²U-containing RNA duplexes have yet been reported. We present here two high-resolution crystal structures of heptamer RNA duplexes (5′-uagc<b><u>s</u></b>^{<b><u>2</u></b>}<b><u>U</u></b>cc-3′ paired with 3′-aucg<b><u>A</u></b>gg-5′ and with 3′-aucg<b><u>U</u></b>gg-5′) containing s²U:A and s²U:U pairs, respectively. For comparison, we also present the structures of their native counterparts solved under identical conditions. We found that replacing O2 with S2 stabilizes the U:A base pair without any detectable structural perturbation. In contrast, an s²U:U base pair is strongly stabilized in one specific U:U pairing conformation out of four observed for the native U:U base pair. This s²U:U stabilization appears to be due at least in part to an unexpected sulfur-mediated hydrogen bond. This work provides additional insights into the effects of 2-thio-uridine on RNA base pairing

Nature’s Selection of Geranyl Group as a tRNA Modification: The Effects of Chain Length on Base-Pairing Specificity

The recently discovered geranyl modification on the 2-thio position of wobble U34 residues in tRNA^Glu, tRNA^Lys, and tRNA^Gln in several bacteria has been found to enhance the U:G pairing specificity and reduce the frameshifting error during translation. It is a fundamentally interesting question why nature chose a C10 terpene group in tRNA systems. In this study, we explore the significance of the terpene length on base-paring stability and specificity using a series of 2-thiouridine analogues containing different lengths of carbon chains, namely, methyl- (C1), dimethylallyl- (C5), and farnesyl-modified (C15) 2-thiothymidines in a DNA duplex. Our thermal denaturation studies indicate that the relatively long chain length of ≥ C10 is required to maintain the base-pairing discrimination of thymidine between G and A. The results from our molecular dynamics simulations show that in the T:G-pair-containing duplex, the geranyl and farnesyl groups fit into the minor groove and stabilize the overall duplex stability. This effect cannot be achieved by the shorter carbon chains such as methyl and dimethylallyl groups. For a duplex containing a T:A pair, the terpene groups disrupt both hydrogen bonding and stacking interactions by pushing the opposite A out of the helical structure. Overall, as the terpene chain length increases, the xT:G pair stabilizes the duplex, whereas the xT:A pair causes destabilization, indicating the evolutionary significance of the long terpene group on base-pairing specificity and codon recognition

DataSheet1_Structural effects of inosine substitution in telomeric DNA quadruplex.docx

The telomeric DNA, a distal region of eukaryotic chromosome containing guanine-rich repetitive sequence of (TTAGGG)n, has been shown to adopt higher-order structures, specifically G-quadruplexes (G4s). Previous studies have demonstrated the implication of G4 in tumor inhibition through chromosome maintenance and manipulation of oncogene expression featuring their G-rich promoter regions. Besides higher order structures, several regulatory roles are attributed to DNA epigenetic markers. In this work, we investigated how the structural dynamics of a G-quadruplex, formed by the telomeric sequence, is affected by inosine, a prevalent modified nucleotide. We used the standard (TTAGGG)n telomere repeats with guanosine mutated to inosine at each G position. Sequences (GGG)4, (IGG)4, (GIG)4, (GGI)4, (IGI)4, (IIG)4, (GII)4, and (III)4, bridged by TTA linker, are studied using biophysical experiments and molecular modeling. The effects of metal cations in quadruplex folding were explored in both Na+ and K+ containing buffers using CD and UV-melting studies. Our results show that antiparallel quadruplex topology forms with the native sequence (GGG)4 and the terminal modified DNAs (IGG)4 and (GGI)4 in both Na+ and K+ containing buffers. Specifically, quadruplex hybrid was observed for (GGG)4 in K+ buffer. Among the other modified sequences, (GIG)4, (IGI)4 and (GII)4 show parallel features, while (IIG)4 and (III)4 show no detectable conformation in the presence of either Na+ or K+. Our studies indicate that terminal lesions (IGG)4 and (GGI)4 may induce certain unknown conformations. The folding dynamics become undetectable in the presence of more than one inosine substitution except (IGI)4 in both buffer ions. In addition, both UV melting and CD melting studies implied that in most cases the K+ cation confers more thermodynamic stability compared to Na+. Collectively, our conformational studies revealed the diverse structural polymorphisms of G4 with position dependent G-to-I mutations in different ion conditions.</p

Multiplexed Activity of perAuxidase: DNA-Capped AuNPs Act as Adjustable Peroxidase

In this study, we have investigated the intrinsic peroxidase-like activity of citrate-capped AuNPs (perAuxidase) and demonstrated that the nanozyme function can be multiplexed and tuned by integrating oligonucleotides on a nanoparticle surface. Systematic studies revealed that by controlling the reaction parameters, the mutiplexing effect can be delayed or advanced and further used for aptasensor applications

Construction and structure studies of DNA-bipyridine complexes as versatile scaffolds for site-specific incorporation of metal ions into DNA

<p>The facile construction of metal–DNA complexes using ‘Click’ reactions is reported here. A series of 2′-propargyl-modified DNA oligonucleotides were initially synthesized as structure scaffolds and were then modified through ‘Click’ reaction to incorporate a bipyridine ligand equipped with an azido group. These metal chelating ligands can be placed in the DNA context in site-specific fashion to provide versatile templates for binding various metal ions, which are exchangeable using a simple EDTA washing-and-filtration step. The constructed metal–DNA complexes were found to be thermally stable. Their structures were explored by solving a crystal structure of a propargyl-modified DNA duplex and installing the bipyridine ligands by molecular modeling and simulation. These metal–DNA complexes could have wide applications as novel organometallic catalysts, artificial ribonucleases, and potential metal delivery systems.</p