A library of triazole-based telomeric quadruplex-selective ligands has been developed that mimic an established family of tri-substituted acridine-based ligands, using crystal structure data as a starting-point for computer-based design. Binding affinities, estimated by electrospray mass spectrometry, are in accord with the design concept.Oligonucleotides and nucleic acids containing G-tracts can be organised as G-quadruplexes. 1 These are polymorphic tertiary structures, characterised by a hydrophobic core of G-quartets and negatively-charged loops. Quadruplexes show exceptional stability over other conformations in the presence of Na + or K + ions. Putative quadruplex sequences have been identified in G-rich genomic sequences, 2 with over-representation in telomeres, 3 as well as in other genomic regions for example in promoter sequences of a number of proto-oncogenes, 4 such as c-myc 5a and c-kit, 5b in 5 0 untranslated regions 6a and in introns. 6b A number of these putative quadruplexes are appealing targets for cancer therapeutics. For instance, inducing the single-stranded telomeric DNA overhang to fold into G-quadruplexes has been shown to inhibit telomerase activity 7a and cancer cell growth. 7b Such precise targeting of human telomeres is significant since in >80% of cancers telomerase is up-regulated and contributes to the malignant phenotype by maintaining cancer cell immortalization. 7c A considerable number of small organic molecules have been found to stabilise quadruplex DNA structures. 8 Many, though not all, are based on polycyclic heteroaromatic cores, with the acridine nucleus being especially well explored. 9 However, the selectivity of many of these molecules for G-quadruplexes over duplex DNA is frequently less than what would be therapeutically acceptable, and their polycyclic features can make their druggability a challenge.The 3,6,9-trisubstituted acridine ligand BRACO-19 ( Fig. 1) has high affinity for human telomeric quadruplex DNAs and is a potent inhibitor of the telomerase enzyme. 10 It has selective cytotoxic activity against a range of human tumour cell lines and shows antitumour activity against xenograft models. 11 The BRACO-19 molecule was designed using qualitative molecular modeling, with the crystal structure of the native parallel human telomeric quadruplex as a template. It was rationalized that each of the three substituents emanating from the acridine core of BRACO-19 would be able to interact with a quadruplex groove. 10 This feature would, it was suggested, provide binding selectivity over duplex DNA, which has just two grooves. A more recent crystal structure of a BRACO-19 complex with a bimolecular quadruplex has confirmed the essential correctness of this hypothesis and has also provided a more detailed view of the interactions involved. 12 The structure has a parallel-stranded quadruplex arrangement, with the biological unit being two 5 0 to 3 0 stacked quadruplexes. Each bimolecular quadruplex in this structure contains three planar stacked G-quartets with a BR...

The proposed antiemetic protocol is effective for controlling vomiting in chemotherapy regimens with an HL of 1-3. For highly emetogenic regimens, the antiemetic protocol is also effective, but protection is not complete. This protocol seems less effective for controlling nausea, although this is a subjective symptom which is difficult to assess and not routinely measured in clinical trials.

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We evaluated the effects of glucomannan or glucomannan plus spirulina-restructured pork (RP) on liver fatty acid profile, desaturase/elongase enzyme activities and oxidative status of Zucker fa/fa rats for seven weeks. Control (C), glucomannan (G) and glucomannan/spirulina (GS)-RP; HC (cholesterol-enriched control), HG and HGS (cholesterol-enriched glucomannan and glucomannan/spirulina-RP) experimental diets were tested. Increased metabolic syndrome markers were found in C, G and GS rats. Cholesterol feeding increased liver size, fat, and cholesterol and reduced antioxidant enzyme levels and expressions. Cholesterolemia was lower in HG and HGS than in HC. GS vs. G showed higher stearic but lower oleic levels. SFA and PUFA decreased while MUFA increased by cholesterol feeding. The arachidonic/linoleic and docosahexaenoic/alpha-linolenic ratios were lower in HC, HG, and HGS vs. C, G, and GS, respectively, suggesting a delta-6-elongase-desaturase system inhibition. Moreover, cholesterol feeding, mainly in HGS, decreased low-density-lipoprotein receptor expression and the delta-5-desaturase activity and increased the delta-9-desaturase activity. In conclusion, the liver production of highly unsaturated fatty acids was limited to decrease their oxidation in presence of hypercholesterolaemia. Glucomannan or glucomannan/spirulina-RP has added new attributes to their functional properties in meat, partially arresting the negative effects induced by high-fat-high-cholesterol feeding on the liver fatty acid and antioxidant statuses.

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