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(24) Such studies revealed that azidothymidine ( AZT) was able to decrease the de novo telomere addition, thus resulting in shortening of telomeres. (23) The first study of this type was conducted by Blackburn in 1994 on the ciliated protozoan Tetrahymena thermophila which is quite rich in telomeres. (23) In particular, chain-terminator reverse-transcriptase inhibitors have been explored as antitumor agents.
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(11−13)īy making use of the DNA polymerase activity of the telomerase, nucleoside and nucleotide analogues have been extensively investigated as potential inhibitors. (9,10) Besides the canonical function of telomere elongation, the telomerase enzymes (EC 2.7.7.49) were also found to act as transcriptional regulators of the Wnt/β-catenin signaling pathway, thus suggesting a role in determining cell growth, differentiation, and apoptosis via a nontelomer-dependent manner. (4,5) This enzyme is normally highly active in adult germ line and stem cells, whereas it is poorly or not expressed at all in the somatic ones. (5−8) The former are mainly responsible for maintaining the telomere structure and its signaling functions, whereas the latter for synthetizing new telomeric DNA strands from its own RNA template. (4) Human telomeres are composed of repetitive, noncoding hexameric nucleotide repeats in complex with the telomere-associated proteins (i.e., the shelterin proteins) and the telomerase.
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The state-of-the-art knowledge on telomeres accounts for rather complicated and highly dynamic structures which are evolutionarily conserved among the eukaryotic cells. High-resolution X-ray crystallography on selected derivatives in the adduct with hCA II as a model study allowed to determine their binding modes and thus to set the structural determinants necessary for further development of compounds selectively targeting the tumoral cells. Compounds 1b, 7b, 8b, and 11b showed good in vitro inhibition potency against the CAs IX and XII, with K I values in the low nanomolar range, and strong antitelomerase activity in PC-3 and HT-29 cells (IC 50 values ranging from 5.2 to 9.1 μM). In this context, we exploited the validated antitumor targets carbonic anhydrases (CAs EC 4.2.1.1) IX and XII to attain the first proof of concept on CA–telomerase dual-hybrid inhibitors. Better outcomes were observed within a multipharmacological approach instead. Telomerase inhibitors (i.e., azidothymidine) can represent promising antitumor agents, although showing high toxicity when administered alone. (Note: monthly uniques is different from total page views.Cancer cells rely on the enzyme telomerase (EC 2.7.7.49) to promote cellular immortality. So what are the most popular porn sites on the internet? Here are some of the most popular ones, based on U.S. Not to mention that you can direct message the performers on these sites.) Sites like OnlyFans and JustforFans are great ways to support your favorite erotic content creators and help guarantee that they will keep making videos for years to come. (PSA: Adult performers are people, too, and if you want high-quality content, you should pay for it.
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