Abstract
A small library of 3’-deoxy-C3’-substituted xylofuranosyl-pyrimidine nucleoside analogues were prepared by photoinduced thiol-ene addition of various thiols, including normal and branched alkyl-, 2-hydroxyethyl, benzyl-, and sugar thiols, to 3’-exomethylene derivatives of 2’,5’-di-O-tert-butyldimethylsilyl-protected ribothymidine and uridine. The bioactivity of these derivatives was studied on tumorous SCC (mouse squamous carcinoma cell) and immortalized control HaCaT (human keratinocyte) cell lines. Several alkyl-substituted analogues elicited promising cytostatic activity in low micromolar concentrations with a slight selectivity toward tumor cells. Near-infrared live-cell imaging revealed SCC tumor cell-specific mitotic blockade via genotoxicity of analogue 10, bearing an n-butyl side chain. This analogue essentially affects the chromatin structure of SCC tumor cells, inducing a condensed nuclear material and micronuclei as also supported by fluorescent microscopy. The results highlight that thiol-ene chemistry represents an efficient strategy to discover novel nucleoside analogues with non-natural sugar structures as anticancer agents.
Highlights
Nucleoside analogues play pivotal roles in antiviral [1,2,3,4] and anticancer [4,5] chemotherapy.They are chemically modified analogues of natural nucleosides, which are endogenous compounds involved in many essential cellular processes, such as DNA and RNA synthesis, cell signaling and metabolism
Parallel experiments were done in the same CO2 incubator, using two custom-built inverted microscope equipped with sensitive charge-coupled device (CCD) sensors. Using this Time-Lapse System (TLS), we studied the effect of compound 10 in 17.0 μM concentration, which is the half maximal inhibitory concentration (MIC50 ) of 10 against squamous cell carcinoma (SCC) cells
The cytotoxic/cytostatic activities of these compounds were studied on tumorous SCC and healthy HaCaT cell lines
Summary
Nucleoside analogues play pivotal roles in antiviral [1,2,3,4] and anticancer [4,5] chemotherapy They are chemically modified analogues of natural nucleosides, which are endogenous compounds involved in many essential cellular processes, such as DNA and RNA synthesis, cell signaling and metabolism. There are more than 10 approved nucleoside derivatives used to treat various cancers, and many other nucleoside analogues are being investigated in clinical trials. Most of these derivatives act as antimetabolites, compete with natural nucleosides, and interact with a large number of intracellular targets inducing cytotoxicity. Some examples for 2’-modified nucleosides approved for the treatment of hematological malignancies include cytarabine (1-β-d-arabinofuranosylcytosine), fludarabine (9-β-d-arabinofuranosyl-2-fluoroadenine), Molecules 2019, 24, 2173; doi:10.3390/molecules24112173 www.mdpi.com/journal/molecules
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