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The dynamic landscape of non-canonical DNA G-quadruplex (G4) folding into G-triplex intermediates has led to the study of G-triplex structures and their ability to serve as peroxidase-mimetic DNAzymes. Here we report the formation, stability, and catalytic activity of a 5′-truncated c-MYC promoter region G-triplex, c-MYC-G3. Through circular dichroism, we demonstrated that c-MYC-G3 adopts a stable, parallel-stranded G-triplex conformation. The chemiluminescent oxidation of luminol by the peroxidase mimicking DNAzyme activity of c-MYC-G3 was increased in the presence of Ca2+ ions. We utilized surface plasmon resonance to characterize both c-MYC-G3 G-triplex formation and its interaction with hemin. The detailed study of c-MYC-G3 and its ability to form a G-triplex structure and its DNAzyme activity identifies issues that can be addressed in future G-triplex DNAzyme designs. [ABSTRACT FROM AUTHOR]

A flexible and modular peptide modeling set was designed using freely available software tools. The set consists of space-filling models of all 20 naturally occurring amino acid side chains and a modular kit for constructing peptides employing C-alpha carbons and amide bond groups. Connectors that allow free rotation about phi and psi angles on the peptide, together with explicit representation of peptide backbone hydrogen bond donor and acceptors allows for the construction of a wide range of protein secondary structure motifs. The space-filling side chain models highlight the steric, acid-base, and polarity of these groups. These models were printed using relatively affordable commercially available fused filament fabrication printers with minimal postprinting processing. Use of these models in student group activities focused on amino acids and protein secondary structural features is described.

Caffeic acid phenethyl ester (CAPE) is a phenolic natural product with a wide range of biological activities, including anticancer activity; however, the ester group of CAPE is metabolically labile. The corresponding amide, CAPA, has improved metabolic stability but limited anticancer activity relative to CAPE. We report the synthesis using flow and on-water Wittig reaction approaches of five previously reported and five novel CAPA analogues. All of these analogues lack the reactive catechol functionality of CAPA and CAPE. Cytotoxicity studies of CAPE, CAPA, and these CAPA analogues in HeLa and BE(2)-C cells were carried out. Surprisingly, we found that CAPA is cytotoxic against the neuroblastoma BE(2)-C cell line (IC50 = 12 µM), in contrast to the weak activity of CAPA against HeLa cells (IC50 = 112 µM), and the literature reports of the absence of activity for CAPA against a variety of other cancer cell lines. One novel CAPA analogue, 3f, was identified as having cytotoxic activity similar to CAPE in HeLa cells (IC50 = 63 µM for 3f vs. 32 µM for CAPE), albeit with lower activity against BE(2)-C cells (IC50 = 91 µM) than CAPA. A different CAPA analogue, 3g, was found to have similar effects against BE(2)-C cells (IC50 = 92 µM). These results show that CAPA is uniquely active against neuroblastoma cells and that specific CAPA analogues that are predicted to be more metabolically stable than CAPE can reproduce CAPA's activity against neuroblastoma cells and CAPE's activity against HeLa cells. [ABSTRACT FROM AUTHOR]

The synthesis and DNA cleavage chemistry of a series of pyridinium skipped aza-enediyens (2-alkynyl-N-propargyl pyridinium salts) is described. It is showed that for this heterocyclic system, efficient DNA cleavage requires the presence of the skipped aza-enediyne functionality and that optimal DNA cleavage is observed for an analogue bearing a p-methoxyphenyl group on the pyridinium 2-alkyne substituent.

The thermal rearrangements of 1,2-dialkynylimidazoles have been shown to lead to trapping products of cyclopenta[ b ]pyrazine carbene intermediates. Here we show that a similar rearrangement also occurs in the case of 1,2-diethynyl-1 H -pyrrole, and that trapping the intermediate cyclopenta[ b ]pyridine carbene with solvent THF affords an ylide that undergoes a Stevens rearrangement to a spirocyclic product. An analogous rearrangement and trapping is observed for thermolysis of 1,2-dialkynylimidazoles in THF or 1,4-dioxane. [ABSTRACT FROM AUTHOR]

Plant polyphenols, such as the African potato (Hypoxis hemerocallidea)-derived bis-catechol rooperol, can display promising anticancer activity yet suffer from rapid metabolism. Embarking upon a program to systematically examine potentially more metabolically stable replacements for the catechol rings in rooperol, we report here a general, scalable synthesis of rooperol and analogues that builds on our previous synthetic approach incorporating a key Pd-catalyzed decarboxylative coupling strategy. Using this approach, we have prepared and evaluated the cancer cell cytotoxicity of rooperol and a series of analogues. While none of the analogues examined here were superior to rooperol in preventing the growth of cancer cells, analogues containing phenol or methylenedioxyphenyl replacements for one or both catechol rings were nearly as effective as rooperol. [ABSTRACT FROM AUTHOR]

Results show that the 3,4,9,10-perylenetetracarboxylic acid diimide ligands bearing basic side chains bind to G-quadruplex DNA. The selectivity between the G-quadruplex DNA and double-stranded DNA binding is influenced by pH-dependent aggregation of the ligands, which favors the binding of the former.

Selectivity, binding stoichiometry, and mode of binding of Tel01, distamycin A, and diethylthiocarbocyanine iodide (DTC) to the parallel stranded G4-quadruplex [[d([T.sub.2][G.sub.5]T)].sub.4] were investigated by ESI-MS. The first drug/ quadruplex complexes observed by ESI-MS are described. Tel01, distamycin A, and DTC all form complexes with quadruplex DNA, but only Tel01 is completely selective for quadruplex versus duplex oligonucleotide under the conditions employed. Previous solution determinations of the binding mode of Tel01 and distamycin A to quadruplex oligonucleotides indicate that Tel01 interacts through end-stacking with guanine tetrads of quadruplex DNA, while distamycin A interacts by binding to quadruplex grooves. When these two different drug/quadruplex complexes are subjected to collisionally activated dissociation in a mass spectrometer, the observed fragmentation patterns are distinct. Tel01/quadruplex complexes undergo facile loss of drug and dissociation to single-strand oligonucleotide ions, while distamycin/quadruplex complexes fragment into single-strand oligonucleotide ions in which the drug molecule is retained. Dissociation patterns for DTC/quadruplex complexes are similar to those of distamycin; therefore, it is concluded that DTC interacts with [[d([T.sub.2][G.sub.5]T)].sub.4] through groove-binding. These ESI-MS results are applicable to both the identification and characterization of G-quadruplex interactive agents and may also be useful in probing unusual DNA structures.

The heterocyclic compound AZB002, containing aza-enediyne, interacts with DNA leading to a frank strand scission of the supercoiled DNA to form two or more DNA adducts. The analogues lacking the aza-enediyne functions either fail to interact with DNA or cleave DNA at guanine residues. The latter two compounds also exhibit cytotoxicity.

Telomeres are important nucleoprotein structures with many functions, such as ensuring the complete replication of chromosomal DNA. Telomeric DNA in vertebrates has a double stranded region made from the TTAGGG repeat sequence and a single-stranded 3'-end overhang. The TTAGGG tail of human telomeric DNA can form stable G-quadruplex structures. Structural studies of parallel G-quadruplex binding by the telomerase-inhibiting compound N,N'-bis(2-(1-piperidino)-ethyl)-3,4,9,10-perylenetetracharboxylic dimide are presented.

A method for the synthesis of 3-ene-1,5-diyne crown ether was developed based on two different synthetic approaches involving a carbenoid coupling reaction of propargyl bromides. The carbenoid coupling of reaction of propargyl bromide was utilized to simultaneously construct the enediyne moiety and effect a macrocyclization of an acyclic dibromide to a 24-membered crown ether. The resulting 3-ene-1,5-diyne crown ether undergoes Bergman cyclization in DMSO/1,4-cyclohexadiene to produce a known omicron-xylyl crown ether.

A method for the synthesis of 3-ene-1,5-diyne crown ether was developed based on two different synthetic approaches involving a carbenoid coupling reaction of propargyl bromides. The carbenoid coupling of reaction of propargyl bromide was utilized to simultaneously construct the enediyne moiety and effect a macrocyclization of an acyclic dibromide to a 24-membered crown ether. The resulting 3-ene-1,5-diyne crown ether undergoes Bergman cyclization in DMSO/1,4-cyclohexadiene to produce a known omicron-xylyl crown ether.

The stability of the G-quadruplex structure formed by deoxyribonucleic acid (DNA) from the DNA.Ribonucleic acid (RNA) hybrid was analyzed to determine the mechanisms that mediate the unwinding of the telomere product. Thermally-induced hybrid to G-quadruplex transitions are mediated by K+ which induces the synthesis of stable G-quadruplex structures in buffer solutions. The effects of K+ during G-quadruplex transitions also indicate the possible formation of short telomeres in microenvironmental conditions.

The photochemical decomposition of the quinobenzoxazines is examined to find evidence for the formation of 2:2 quinobenzoxazine-Mg2+ dimers and the 2:2 drug-Mg2+ complex on duplex DNA. It was found that the quinobenzoxazine A-62176 is photoreactive in visible light, which accelerates by nearly 500 times in the presence of the electron transfer mediator methyl viologen. Photoreaction rates of racemic amd scalemic A-62176 in the presence of Mg2+ and the achiral fluoroquinolone norfloxacin, as accelerated by MV2+, were observed to be different, indicating the formation of homochiral and heterochiral 2:2 drug-Mg2+ dimers in solution.

The ligand N,N'-bis( N-p-guanidinobenzyl-N-methyl aminocarbonyl)-1,3- diaminobenzene, 'BIGBEN,' associates to the minor groove of the receptor d(CGCGAATTCGCG)2 dodecamer at the AT rich site as detected by two-dimensional nuclear magnetic resonance spectroscopy. Vigorous interactions are observed among the protons of the DNA and the exchangeable and nonexchangeable protons of the BIGBEN ligand.

Restrained molecular dynamics measurements and NMR spectroscopy help analyze the three-dimensional solution structure of a tridecamer DNA duplex sequence, present in the conserved domain of HIV-1 genome's long hindermost repeat. The structure is contracted more longitudinally than the classical B-DNA, and many base pairs show considerable propellar twist. Compared to the CTTG-pyr sequence, the - CTTG-pur sequence has a greater roll and slide for the TG step.

A conserved sequence in the long terminal repeat of the HIV genome is identified. This sequence can be used as a pattern in designing drugs that will inhibit transcription and even reverse transcription. Proton nuclear magnetic resonance for the this conserved sequence is assigned using a synthetic DNA duplex. Two-dimensional nuclear Overhauser enhancement and double-quantum-filtered correlation spectral analyses were also employed to determine distance and torsion angle constraints.

The article explains the various mechanisms that are involved in the reactions of 1-alkynylimidazoles. The production of different products due to the presence of different bases or gold in the system is also demonstrated.

A study was conducted to explore the ability of G-quadruplex DNA structures to unwind a prototypical replicate helicase, SV40 large T-antigen (T-ag). The findings demonstrate that the G-quadruplex helicase activity is robust and comparable to the duplex helicase activity of T-ag which could be used to study activity of SV40 replication.

Electrospray ionization mass spectrometry (ESI-MS) is employed to investigate the interactions between the stable trioxatriangulenium ion (TOTA) and duplex DNA or G-quadruplex DNA. It is also shown that 5'-GGG-3' triads and 5'-GGG-3' tetrads in duplex DNA consisting of telomeric T2AG3 or T2G4 repeats are preferentially photocleaved with a characteristic pattern, in agreement with the observations of guanine radical cation trapping.