No abstract

Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of numerous chalcone derivatives. In fact, structural features of chalcones are easy to construct from simple aromatic compounds, and it is convenient to perform structural modifications to generate functionalized chalcone derivatives. Many of these synthetic analogs were shown to possess similar bioactivities as their natural counterparts, but often with an enhanced potency and reduced toxicity. This review article aims to demonstrate how bioinspired synthesis of chalcone derivatives can potentially introduce a new chemical space for exploitation for new drug discovery, justifying the title of this article. However, the focus remains on critical appraisal of synthesized chalcones and their derivatives for their bioactivities, linking to their interactions at the biomolecular level where appropriate, and revealing their possible mechanisms of action.

No abstract

Immunoslot blot assays have been used for the analysis of many DNA adducts but problems are frequently encountered in achieving reproducible results. Each step of the assay has been systematically examined and it was found that the major problems are in the DNA fragmentation step and the use of the manifold apparatus. Optimisation was performed upon both the malondialdehyde-deoxyguanosine adduct (M 1 dG) and the O 6 -carboxymethyldeoxyguanosine adduct (O 6 CMdG) to demonstrate the applicability to other DNA adducts.Blood samples from the EPIC study (n = 162) were analysed for M 1 dG adducts and the data showed no correlation with adduct levels in other tissues indicating that the EPIC blood samples were not useful for studying M 1 dG adducts. Blood samples from a processed meat vs vegetarian diet intervention (n = 6) were analysed for O 6 CMdG and many were below the limit of detection. The reduction of background adduct levels in standard DNA was investigated using chemical and whole-genome amplification approaches. The latter gave a sensitivity improvement of 2.6 adducts per 10 7 nucleotides for the analysis of O 6 CMdG.Subsequent reanalysis for O 6 CMdG showed a weakly significant increase in O 6 CMdG on the processed meat diet compared with the vegetarian diet, demonstrating that further studies are warranted.

Novel, reproducible, and accurate LC/MS/MS methods were developed for the determination of the urinary content of O(6)CMG and O(6)CMdG, and of the possible formation of O(6)MeG and O(6)MedG by decarboxylation. Clinical samples from volunteers on different diets were analysed. Further studies are required to discover a link between the presence of these biomarkers in urine and red meat consumption.

To accurately quantify the number of single-strand breaks (SSBs) induced in plasmid DNA molecules after irradiation, a new type of assay methodology has been explored. The new method is based on the TUNEL (terminal deoxynucleotide transferase dUTP nick end-labeling) assay that was adopted for use under ELISA (enzyme-linked immunosorbent assay) conditions. The assay was found to both improve the quantification and reduce the uncertainties in measurement of SSBs compared with the commonly used agarose gel electrophoresis (AGE) method. Together with AGE, the new method can provide the additional data necessary for an accurate analysis of both SSB and double-strand break (DSB) formation in DNA molecules after irradiation. Furthermore, since only small amounts of DNA are required, the ELISA method can be used to quantify the damage in samples of DNA that are smaller than those required for AGE analysis. As an example of the data obtainable using the new method, plasmid DNA samples were irradiated with vacuum-ultraviolet (VUV) light in an aqueous solution at 170 nm and subsequently analyzed by ELISA. The results were compared directly with those from AGE analysis. The ELISA gave results for SSBs that were an order of magnitude higher than those from AGE and suggested that DSBs are more likely to be the result of two SSBs rather than a single event and that a damaged molecule is more likely to be susceptible to VUV light than an undamaged one.

Covalent binding of endo-or exogenous chemicals to DNA results in the formation of DNA adducts which are reflective of exposure of the human body to DNA-damaging molecules and their metabolic pathways. The study of DNA adduct types and levels in human tissue therefore offers an interesting tool in several fields of research, including toxicology and cancer epidemiology. Over the years, a range of techniques and methods have been developed to study the formation of endo-and exogenous DNA adducts. However, for the simultaneous detection, identification and quantification of both known and unknown DNA adducts, mass spectrometry (MS) is deemed to be the most promising technique. In this perspective, we focus on the analysis of multiple DNA adducts within a sample with the emphasis on untargeted analysis. The advantageous use of MS methodologies for DNA adductome mapping is discussed comprehensively with relevant field examples. In addition, several aspects of study design, sample pretreatment and analysis are addressed as these factors significantly affect the reliability of DNA adductomics studies.

The present study established an impurity profile of a synthetic route to the hallucinogenic N,N-dimethyltryptamine (DMT). The synthesis was carried out under reductive amination conditions between tryptamine and aqueous formaldehyde in the presence of acetic acid followed by reduction with sodium cyanoborohydride. Analytical characterization of this synthetic route was carried out by gas chromatography ion trap mass spectrometry using electron- and chemical-ionization modes. Methanol was employed as a liquid CI reagent and the impact of stoichiometric modifications on side-products formation was also investigated. Tryptamine 1, DMT 2, 2-methyltetrahydro-β-carboline (2-Me-THBC, 3), N-methyl-N-cyanomethyltryptamine (MCMT, 4), N-methyltryptamine (NMT, 5), 2-cyanomethyl-tetrahydro-β-carboline (2-CM-THBC, 6) and tetrahydro-β-carboline (THBC, 7) have been detected under a variety of conditions. Replacement of formaldehyde solution with paraformaldehyde resulted in incomplete conversion of the starting material whereas a similar replacement of sodium cyanoborohydride with sodium borohydride almost exclusively produced THBC instead of the expected DMT. Compounds 1 to 7 were quantified and the limits of detection were 28.4, 87.7, 21.5, 23.4, 41.1, 36.6, and 34.9 ng mL(-1), respectively. The limits of quantification for compounds 1 to 7 were 32.4, 88.3, 25.4, 24.6, 41.4, 39.9, and 37.0 µg mL(-1), respectively. Linearity was observed in the range of 20.8-980 µg mL(-1) with correlation coefficients > 0.99. The application holds great promise in the area of forensic chemistry where development of reliable analytical methods for the detection, identification, and quantification of DMT are crucial and also in pharmaceutical analysis where DMT might be prepared for use in human clinical studies.