Abstract
Cancer cells rely on the enzyme telomerase (EC 2.7.7.49) to promote cellular immortality. Telomerase inhibitors (i.e., azidothymidine) can represent promising antitumor agents, although showing high toxicity when administered alone. Better outcomes were observed within a multipharmacological approach instead. 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. Compounds 1b, 7b, 8b, and 11b showed good in vitro inhibition potency against the CAs IX and XII, with KI values in the low nanomolar range, and strong antitelomerase activity in PC-3 and HT-29 cells (IC50 values ranging from 5.2 to 9.1 μM). 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.
Highlights
Eukaryotic cells do possess limited replicative potential as progressive shortage of the chromosome ends takes place after every duplication cycle.[1]
We performed a copper-catalyzed azide−alkyne cycloaddition (CuAAC) between the azide of the reverse-transcriptase inhibitor AZT with the terminal alkyne pendant installed on various CAI scaffolds (Figure 1)
We investigated hTERT expression in cells incubated with CA−telomerase dual smallmolecule inhibitors (CAI−TI)
Summary
Eukaryotic cells do possess limited replicative potential as progressive shortage of the chromosome ends (i.e., the telomeres) takes place after every duplication cycle.[1]. 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.[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.[4,5] 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.[9,10] Besides the canonical function of telomere elongation, the telomerase enzymes (EC 2.7.7.49) were found to act as transcriptional regulators of the Wnt/β-catenin signaling pathway, suggesting a role in determining cell growth, differentiation, and apoptosis via a nontelomerdependent manner.[11−13]
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