Calcium-Dependent Chemiluminescence Catalyzed by a Truncated c-MYC Promoter G-Triplex DNA.

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 promoter region G-triplex, c-MYC-G3. Through circular dichroism, we demonstrated that c-MYC-G3 adopts a stable, parallel-stranded G-triplex conformation.

Flow and On-Water Synthesis and Cancer Cell Cytotoxicity of Caffeic Acid Phenethyl Amide (CAPA) Derivatives.

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.

Scalable Synthesis and Cancer Cell Cytotoxicity of Rooperol and Analogues.

Plant polyphenols, such as the African potato ()-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.

Flexible and modular 3D-printed peptide models.

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.

N-Methylmesoporphyrin IX Exhibits G-Quadruplex-Specific Photocleavage Activity.

N-Methylmesoporphyrin IX (NMM) has long been known as a G-quadruplex DNA (G4) ligand. However, there has been little investigation into its G-quadruplex photocleavage activity. Herein, we demonstrate that NMM is a highly selective photocleavage agent for G4 structures but not duplex DNA.

Preparation and Utility of -Alkynyl Azoles in Synthesis.

Heteroatom-substituted alkynes have attracted a significant amount of interest in the synthetic community due to the polarized nature of these alkynes and their utility in a wide range of reactions. One specific class of heteroatom-substituted alkynes combines this utility with the presence of an azole moiety. These -alkynyl azoles have been known for nearly 50 years, but recently there has been a tremendous increase in the number of reports detailing the synthesis and utility of this class of compound.

Alternative DNA structure formation in the mutagenic human c-MYC promoter.

Mutation 'hotspot' regions in the genome are susceptible to genetic instability, implicating them in diseases. These hotspots are not random and often co-localize with DNA sequences potentially capable of adopting alternative DNA structures (non-B DNA, e.g.

Synthesis and Evaluation of a Rationally Designed Click-Based Library for G-Quadruplex Selective DNA Photocleavage.

DNA containing repeating G-rich sequences can adopt higher-order structures known as G-quadruplexes (G4). These structures are believed to form within telomeres and the promoter regions of some genes, particularly in a number of proto-oncogenes, where they may play a role in regulating transcription. Alternatively, G4 DNA may act as a barrier to replication.

Development and validation of an LCMS method to determine the pharmacokinetic profiles of caffeic acid phenethyl amide and caffeic acid phenethyl ester in male Sprague-Dawley rats.

A validated LCMS method was developed for the quantitative determination of caffeic acid phenethyl amide (CAPA) and caffeic acid phenethyl ester (CAPE) from rat plasma. Separation was achieved using a reverse-phase C12 HPLC column (150 × 2.00 mm, 4 µm) with gradient elution running water (A) and acetonitrile (B).

A fluorescence-based assay for p38α recruitment site binders: identification of rooperol as a novel p38α kinase inhibitor.

A new p38α inhibitor: Using a D-recruitment site (DRS) probe for p38α which exploits covalent interaction with Cys119 and alkyne-azide "click" chemistry to identify small molecules that recognize the p38α DRS, the anti-inflammatory natural product rooperol was identified as a novel p38α inhibitor.

G-quadruplex DNA cleavage preference and identification of a perylene diimide G-quadruplex photocleavage agent using a rapid fluorescent assay.

A rapid fluorescence assay for G-quadruplex DNA cleavage was used to investigate the preference of TMPyP4 photochemical and Mn·TMPyP4 oxidative cleavage. Both agents most efficiently cleave the c-Myc promoter G-quadruplex. Direct PAGE analysis of selected assay samples showed that for a given cleavage agent, different cleavage products are formed from different G-quadruplex structures.

Synthesis and docking studies of novel antitumor benzimidazoles.

In this work, the benzimidazole-pyrrole conjugates 6a-h and benzimidazole-tetracycles conjugates 12-14 were prepared. The cytotoxicity of the compounds 3, 4a-h, 6a-h, 8, 10 and 12-14 was tested against lung cancer cell line A549. Compound 6b exhibited higher activity than the bis-benzoxazole natural product (UK-1), the standard.

Stability of caffeic acid phenethyl amide (CAPA) in rat plasma.

A validated C₁₈ reverse-phase HPLC method with UV detection at 320 nm was developed and used for the stability evaluation of caffeic acid phenethyl amide (CAPA) and caffeic acid phenethyl ester (CAPE) in rat plasma. CAPA is the amide derivative of CAPE, a naturally occurring polyphenolic compound that has been found to be active in a variety of biological pathways. CAPA has been shown to protect endothelial cells against hydrogen peroxide-induced oxidative stress to a similar degree to CAPE.

Cytotoxic 1,2-dialkynylimidazole-based aza-enediynes: aza-Bergman rearrangement rates do not predict cytotoxicity.

A new class of potential antitumor agents inspired by the enediyne antitumor antibiotics has been synthesized: the 1,2-dialkynylimidazoles. The aza-Bergman rearrangement of these 1,2-dialkynylimidazoles has been investigated theoretically at the B3LYP/6-31G(d,p) level and experimentally by measuring the kinetics of rearrangement in 1,4-cyclohexadiene. There is a good correlation between the theoretical and experimental results; subtle substituent effects on the initial aza-Bergman cyclization barrier predicted by theory are confirmed by experiment.

Synthesis of a series of caffeic acid phenethyl amide (CAPA) fluorinated derivatives: comparison of cytoprotective effects to caffeic acid phenethyl ester (CAPE).

A series of catechol ring-fluorinated derivatives of caffeic acid phenethyl amide (CAPA) were synthesized and screened for cytoprotective activity against H2O2 induced oxidative stress in human umbilical vein endothelial cells (HUVEC). CAPA and three fluorinated analogs were found to be significantly cytoprotective when compared to control, with no significant difference in cytoprotection between caffeic acid phenethyl ester (CAPE) and CAPA.

Cyclization kinetics and biological evaluation of an anticancer 1,2-dialkynylimidazole.

1,2-Dialkynylimidazoles have been reported to undergo thermal cyclization/rearrangement to diradical and carbene intermediates. Optimization of the synthesis of the 1,2-dialkynylimidazole has provided sufficient material for kinetic and biological studies. The 1,2-dialkynylimidazole is cytotoxic against a wide range of cancer cells and induces apoptosis in A549 cells.

Structure-activity relationships in the cytoprotective effect of caffeic acid phenethyl ester (CAPE) and fluorinated derivatives: effects on heme oxygenase-1 induction and antioxidant activities.

To determine the relationship between catechol ring modifications and the activity of caffeic acid phenethyl ester (CAPE) as a cytoprotective agent, six catechol ring-fluorinated CAPE derivatives were evaluated for their cytoprotective abilities, as well as for their antioxidant and heme oxygenase-1 (HO-1) inducing capacity in a human umbilical vein endothelial cell (HUVEC) model of oxidant stress. To ascertain the involvement of HO-1 induction in the cytoprotective effects of CAPE analogues, their ability to induce HO-1 at 20microM was determined by reverse transcriptase polymerase chain reaction, western blotting and the use of HO-1 inhibitor tin protoporphyrin IX. There was significant induction of HO-1 by CAPE derivatives.

Efficient, regioselective access to bicyclic imidazo[1,2-x]- heterocycles via gold- and base-promoted cyclization of 1-alkynylimidazoles.

Reactions of 1-alkynylimidazoles involving the formation of their 2-lithio derivatives followed by addition of aldehydes or ketones are presented. The method gives access to 1-alkynyl-2-(hydroxymethyl)imidazoles which undergo 6-endo-dig or 5-exo-dig cyclization under AuCl(3)- or base-catalyzed conditions to yield imidazo[1,2-c]oxazoles and imidazo[2,1-c][1,4]oxazine heterocycles. Under transition metal catalysis, the reaction occurs in a regiospecific manner, leading exclusively to the product of 6-endo-dig attack, whereas under basic conditions, the reaction takes place in a regioselective manner giving preferentially the product from 5-exo-dig attack.

Synthesis and biological evaluation of p38alpha kinase-targeting dialkynylimidazoles.

Based on the mild, thermal rearrangement of 1,2-dialkynylimidazoles to reactive carbene or diradical intermediates, a series of 1,2-dialkynylimidazoles were designed as potential irreversible p38 MAP kinase alpha-isoform (p38alpha) inhibitors. The synthesis of these dialkynylimidazoles and their kinase inhibition activity is reported. The 1-ethynyl-substituted dialkynylimidazole 14 is a potent (IC(50)=200 nM) and selective inhibitor of p38alpha.

Pharmacokinetics of caffeic acid phenethyl ester and its catechol-ring fluorinated derivative following intravenous administration to rats.

The pharmacokinetic profiles of caffeic acid phenethyl ester (CAPE) and its catechol-ring fluorinated derivative (FCAPE) were determined in rats after intravenous administration of 5, 10 or 20 mg/kg for CAPE and 20 mg/kg for FCAPE, respectively. The plasma concentrations of CAPE and FCAPE were measured using a validated liquid chromatography tandem mass spectrometric method. The pharmacokinetic parameters were estimated using non compartmental analysis (NCA) and biexponential fit.

An improved synthesis of (+/-)-N'-nitrosonornicotine 5'-acetate.

A concise and efficient route to (+/-)-N'-nitrosonornicotine 5'-acetate (NNN-5'-OAc), a stable precursor of the active metabolite 5'-hydroxy(+/-)-N'-nitrosonornicotine NNN-5'-OH is reported. The synthesis utilizes sulfinimine chemistry to give (+/-)-NNN-5'-OAc in 26% yield over 4 steps.

Real-time investigation of SV40 large T-antigen helicase activity using surface plasmon resonance.

The simian virus 40 (SV40) genome is a model system frequently employed for investigating eukaryotic replication. Large T-antigen (T-ag) is a viral protein responsible for unwinding the SV40 genome and recruiting necessary host factors prior to replication. In addition to duplex unwinding T-ag possesses G-quadruplex DNA helicase activity, the physiological consequence of which is unclear.

Synthesis of 2-substituted 9-oxa-guanines {5-aminooxazolo[5,4-d]pyrimidin-7(6H)-ones} and 9-oxa-2-thio-xanthines {5-mercaptooxazolo[5,4-d]pyrimidin-7(6H)-ones}.

Oxazolo[5,4-d]pyrimidines can be considered as 9-oxa-purine analogs of naturally occurring nucleic acid bases. Interest in this ring system has increased due to recent reports of biologically active derivatives. In particular, 5-aminooxazolo[5,4-d]pyrimidine-7(6H)-ones (9-oxa-guanines) have been shown to inhibit ricin.

New transition metal ion complexes with benzimidazole-5-carboxylic acid hydrazides with antitumor activity.

Metal complexes of 2-methyl-1H-benzimidazole-5-carboxylic acid hydrazide (4a; L(1)) and its Schiff base 2-methyl-N-(propan-2-ylidene)-1H-benzimidazole-5-carbohydrazide (5a; L(2)) with transition metal ions e.g., copper, silver, nickel, iron and manganese were prepared.