Antitumor substitution-inert polynuclear platinum complexes stabilize G-quadruplex DNA and suppress G-quadruplex-mediated gene expression

0554901 - BFÚ 2022 RIV GB eng J - Journal Article
Malina, Jaroslav - Kostrhunová, Hana - Farrell, N. - Brabec, Viktor
Antitumor substitution-inert polynuclear platinum complexes stabilize G-quadruplex DNA and suppress G-quadruplex-mediated gene expression.
Inorganic Chemistry Frontiers. Roč. 8, č. 13 (2021), s. 3371-3381. ISSN 2052-1553. E-ISSN 2052-1553
R&D Projects: GA ČR(CZ) GC20-14082J
Institutional support: RVO:68081707
Keywords : myc g-quadruplex * promoter region * phosphate clamp * metal-complexes * nucleic-acids
OECD category: Organic chemistry
Impact factor: 7.779, year: 2021
Method of publishing: Limited access
https://pubs.rsc.org/en/content/articlelanding/2021/QI/D1QI00488C

DNA G-quadruplex (G4) structures formed in the telomeric and promoter regions represent attractive drug targets for anticancer therapy. Thus, much effort has been devoted to the development of a variety of G4-binding ligands, mostly based on rigid planar structures. Here, we investigated the efficacy of inherently flexible anticancer substitution-inert polynuclear platinum(s) complexes (SI-PPCs) to stabilize DNA G4s and terminate DNA polymerization on templates containing G4-forming sequences. Conventional DNA polymerase primer extension assay, fluorescence melting studies, fluorescence indicator displacement assay and circular dichroism spectroscopy revealed that SI-PPCs can stabilize DNA G4s and terminate DNA polymerization on templates containing G4-forming sequences although they lack structural properties of traditional G4 binders. Despite that the selectivity for G4 DNA over double-stranded DNA was somewhat lower than that observed for some traditional G4-binding ligands, it was notable that one of the investigated SI-PPCs, anticancer Triplatin NC, reduced the expression of G4-regulated genes c-myc and c-kit in human embryonic kidney cells. These results demonstrate that the overall biological activity of SI-PPCs can also involve interactions of SI-PPCs with different cellular targets acting as multi-target-directed compounds.
Permanent Link: http://hdl.handle.net/11104/0329516