1,721,217 research outputs found
Human Immunodeficiency Virus (HIV-1) Auxiliary Protein Vif and Cellular APOBEC Deaminases: Their Roles Unveiled?
No full textRepair and Translesion DNA Polymerases as Anticancer Drug Targets
No full textWe have very recently highlighted possible connections between DNA polymerases, the main enzymes in the DNA metabolism, and human diseases (Ramadan, K., Maga, G. and Hübscher, U.: DNA polymerases and diseases, In: Genome Integrity: Facets and Perspectives ed. Lankenau, D.-H. Springer Verlag, Heidelberg Germany, Vol 1, pp. 69-102, 2007). Beside a role in DNA replication of the genome DNA polymerases have fundamental functions in other aspect of DNA metabolism, such as DNA repair, DNA recombination, translesion DNA synthesis and cell cycle checkpoint. In the last decade many novel DNA polymerases have been identified, but their exact cellular functions still await clarification. We know that many DNA polymerases have redundant functions. It is a fact that specific inhibition of certain DNA polymerases is a promising approach to develop anticancer drugs. In this review we will concentrate on DNA repair proteins and translesion DNA polymerases as possible targets for anti cancer drugs
Parallel solution phase synthesis of 4-dialkylamino-2-methylsulfonyl-6-vinylpyrimidines
No full textA simple and straightforward methodology for the parallel, solution-phase synthesis of novel 4-dialkylamino-2-methylsulfonyl-6-vinylpyrimidines 9a-j has been developed. Starting from 2-methylthio-6-[2-(p-toluensulfonyloxy)ethan-1-yl]-4(3H)-pyrimidinone (6), a three-step procedure (namely, tosylate substitution by amines, base-catalyzed rearrangement, and sulfide to sulfone oxidation) using a Buchi Sincore synthesizer gave the final products in high yield after simple ethyl acetate extraction and without further purification. Interestingly, when the final oxidation step was performed on 4-arylpiperazine derivatives 8g-j, the corresponding highly polar piperazine N-oxides 9g-j were obtained, which conversely needed chromatographic purification in order to give the pure products
Identification and quantification of α-dicarbonyl compounds in balsamic and traditional balsamic vinegars and their cytotoxicity against human cells
No full textEight balsamic and five traditional balsamic vinegars from Italy were analyzed to verify the presence of
a-dicarbonyl compounds. The occurrence of glyoxal (GO), methylglyoxal (MGO), 2,3-butanedione (2,3-
BD), 3-deoxyglucosone, 3,4-dideoxyglucosone-3-ene, and hydroxypyruvaldehyde or dihydroxyacetone,
is shown by RP-HPLC–DAD–ESI-MS/MS analysis. Quantification of GO, MGO and 2,3-BD was performed
by a validated RP-HPLC–DAD method. GO, MGO and 2,3-BD were also found in red wine vinegars and in
E150a food additive (caramel), which are used in balsamic vinegar production. Moreover, the cytotoxic
activity of GO, MGO, 2,3-BD subjected to simulated in vitro gastro-duodenal digestion, either as a mixture
or individual compounds, was evaluated against an intestinal (HCT116) human cell line. The toxicity of
these compounds, as far as we could see, seemed to be minimal even after 72 h of continuing exposure
with a 50% decrease of cell vitality toward human cells at concentrations definitely superior to those that
can be taken up with diet. In conclusion, it does not appear that dietary intake of the tested a-dicarbonyl
compounds might be a significant source of toxicity
Current advances in the development of anticancer drugs targeting tyrosine kinases of the Src family
No full textProtein kinases, either membrane-embedded receptorial or cytosolic non-receptorial ones, are important transducers of cell proliferation signals. In almost all tumor cells, the activity of some kinases is deregulated, either because of the presence of cancer-specific aberrant forms, or as a consequence of alterations in regulatory pathways, at the transcriptional or post-transcriptional level, which increase the activity of protein kinases with respect to normal cells. The study of the non-receptor tyrosine kinase Src plays a pivotal role in the field of the mol. genetics of cancer. The Src family of kinases (SFKs) comprises nine members, Src, Fyn, Yes, which are expressed in most tissues, and Blk, Yrk, Fgr, Hck, Lck and Lyn, which are more selectively expressed in particular tissues. To date, cellular (c-) Src has been implicated in the development of human cancer. Like oncogenic v-Src, activated mutants of c-Src can transform cells in culture and induce tumors in chickens. In addn., Src protein expression and/or activity is elevated in epithelial cancers, or cell lines derived from these, and there is often an assocn. with advancement of disease or with malignancy. During the past decade, examples of tyrosine kinases inhibitors have been reported. Many of these compds. were highly active in vitro, but only a few demonstrated in vivo activity. These approaches led to the characterization of the PP1/PP2 derivs. as very strong and selective inhibitors of the c-Src family of kinases. Unfortunately, attempts to improve the biol. profile of the latter compds. have so far met little success. Following these studies, some other inhibitors, possessing different chem. structures and interesting c-Src inhibitory activity, have been recently reported. Some of these mols. showed potent inhibition of tumor cell proliferation, which was due to the interference with the signalling pathway at the level of Src tyrosine kinase, providing proof-of-principle for the targeting of Src in anticancer chemotherapy
The influence of in vitro simulated digestion process on alpha-dicarbonyl compound cytotoxicity
No full textalpha-Dicarbonyl compounds are intermediate substances occurring in thermally treated foods as reaction products of caramelization, Maillard reaction, and lipid peroxidation, in fermented foods and beverages, where are produced by microorganism metabolisms, in plants, produced in response to stress conditions, in water, in tobacco smoke, and in medical products (peritoneal dialysis fluids). Glyoxal (G) and methylglyoxal (MG) can be produced also by many strains of bacteria present in the intestinal tract, and are endogenous compounds because are human physiological metabolites. Alpha-Oxoaldehydes are highly reactive alkilating agents, that have been found to rapidly modify side chains of protein and form reversible Schiff’s base that after subsequent rearrangements, oxidations and dehydratations, yields relatively stable Amadori products, known as Maillard reaction products (MRPs) if occur in foods, or advanced glycation products (AGEs) if are endogenously formed.
Recent publications reported that both alpha-dicarbonyl compounds and AGEs induced several cellular damages, mainly attributed to their interaction with essential cellular macromolecules, leading to the alteration in structure and function of some kind of cells. In recent years the role of exogenous alpha-dicarbonyl compounds in gastrointestinal tract is under investigation to understand whether excess consumption of such dietary compounds might be a risk for human health. Nevertheless, to our knowledge, the influence of the digestion process on food derived alpha-dicarbonyl compounds has not been investigated. Therefore, a mixture of alpha-dicarbonyl compounds, commonly occurring in foods (G, MG and diacetyl), before and after in vitro simulated gastrointestinal digestion process, was evaluated for its ability to induce cytotoxicity against three different cultured cell lines and to inhibit the function of selected enzymes responsible for DNA repair in human cells. Then these properties were correlated both to the alpha-dicarbonyl compound content (determined by a validated RP-HPLC-DAD method) before and after digestion and with the digestive enzyme carbonylation induced by alpha-dicarbonyl compounds. The digested alpha-dicarbonyl mixtures was found to contain compound(s) with apparent selective in vitro antiproliferative activity against colon cancer cells, but not other cell lines. Overall, the results showed that digested alpha-dicarbonyl compounds should not be cytotoxic towards normal cells, but may display specific anticancer activity
N-(thiazol-2-yl)-2-thiophene carboxamide derivatives as Abl inhibitors identified by a pharmacophore-based database screening of commercially available compounds
No full textSuggestions derived from a previous ligand-based ligand design approach and docking calculations aimed at finding compound with affinity toward Abl and molecular scaffolds previously untested as Abl inhibitors, led to the identification of commercially available N-(thiazol-2-yl)-2-thiophene carboxamide derivatives with affinity in a cell-free assay up to low nanomolar concentrations, significantly enhanced with respect to that of their parent compounds previously reported. In particular, among compounds of the Asinex database, molecular docking simulations guided the choice of high-affinity ligands, predicting their binding mode and their interaction pattern with the Abl catalytic binding site. Moreover, affinity of the new compounds was also rationalized in terms of their interactions with the enzyme
Synthesis of pyrazolo[3,4-d]pyrimidine derivatives active against the T315I Abl mutation.
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