Chemistry of glycol nucleic acid (GNA):Synthesis, photophysical characterization and insight into the biological activity of phenanthrenyl GNA constituents

Kowalczyk, Aleksandra, Piotrowicz, Michał, Gapińska, Magdalena, Trzybiński, Damian, Woźniak, Krzysztof, Golding, Taryn M., Stringer, Tameryn ORCID: https://orcid.org/0000-0002-4439-131X, Smith, Gregory S., Czerwieniec, Rafał and Kowalski, Konrad (2022) Chemistry of glycol nucleic acid (GNA):Synthesis, photophysical characterization and insight into the biological activity of phenanthrenyl GNA constituents. Bioorganic Chemistry, 125. ISSN 0045-2068

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Abstract

The knowledge pertaining to the chemistry and biological activity of glycol nucleic acid (GNA) components, like nucleosides and nucleotides, is still very limited. Herein we report on the preparation of the uracil nucleoside (1) and nucleotide ester GNA (2). The compounds are functionalised with a luminescent phenanthrenyl group. In DMSO, 1 and 2 are brightly fluorescent, with emission maxima at 390 nm, nanosecond decay times (0.6 and 0.75 ns, respectively), and quantum yields of ca. 0.2. In the solid phase, they show excimeric emission, with maxima at 495 nm (1) and 432 nm (2), and decay times of 3.7 ns (1) and 2.9 ns (2). The anticancer activity of the GNA components, as well as gemcitabine hydrochloride, used as a reference drug, were examined in vitro against human cancer HeLa and Ishikawa cells, as well as against normal L929 cells, using a battery of biochemical assays. Furthermore, biodistribution imaging studies were carried out in HeLa cells, with luminescence confocal microscopy, which showed that the compounds localized mainly in the lipophilic cellular compartments. Nucleoside (1) and nucleotide ester (2) features two different anticancer activity profiles. At 24 h of treatment, the nucleoside acts mainly as a toxin and induces necrosis in HeLa cells, whereas the nucleotide ester exhibits pro-apoptotic activity. At longer treatment times (72 h), the nucleoside and the reference, gemcitabine hydrochloride, featured almost identical signs of anticancer activity, such as S-phase cell cycle arrest, proliferation inhibition, and apoptosis induction. In view of this data, one can hypothesize that despite the structural differences, the newly obtained phenanthrenyl GNA nucleoside (1) and gemcitabine may share a common mechanism of anticancer activity in HeLa cancer cells. The GNA components were also examined as antiplasmodial agents against Plasmodium falciparum, in vitro. Nucleoside (1) was found to be more potent than nucleotide (2), displaying activity in the low micromolar range. Furthermore, both phenanthrene derivatives were found to display resistance indices at least 9-fold lower than chloroquine diphosphate (CQDP).

Item Type: Article
Additional Information: Funding Information: K.K. thanks the National Science Center in Cracow, Poland (grant OPUS UMO-2018/29/B/ST5/00055) for financial support. Crystallographic analysis was carried out at the Biological and Chemical Research Centre, University of Warsaw, established within the project co-financed by European Union from the European Regional Development Fund under the Operational Programme Innovative Economy, 2007–2013. The X-ray diffraction data were collected at the Core Facility for Crystallographic and Biophysical Research to support the development of medicinal products sponsored by the Foundation for Polish Science (FNP). R.C. thanks the German Research Foundation (DFG) for support (Project № 389797483 ). G.S.S. would like to thank the University of Cape Town and the National Research Foundation of South Africa (UID: 129288 ) for financial support. Publisher Copyright: © 2022
Uncontrolled Keywords: anticancer,antiplasmodial activity,gna,luminescence,phenanthrene,biochemistry,molecular biology,drug discovery,organic chemistry,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1303
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Depositing User: LivePure Connector
Date Deposited: 19 Jul 2022 13:30
Last Modified: 12 Aug 2022 05:33
URI: https://ueaeprints.uea.ac.uk/id/eprint/86610
DOI: 10.1016/j.bioorg.2022.105847

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