Journal
JOURNAL OF INORGANIC BIOCHEMISTRY
Volume 226, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2021.111660
Keywords
Platinum based drugs; Metalated purines; Nucleoside analogues; Nucleic acids; Antitumor drugs; Antiviral drugs
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This study investigated the uptake of nucleos(t)ide analogues at the plasma membrane level, with findings showing significant cellular uptake of model platinated deoxynucleos(t)ide 1 and 3, while complex 2 was unable to cross the cell plasma membrane. Further experiments supported an uptake mechanism involving Na+-dependent concentrative transporters localized at the plasma membrane level. These findings suggest the potential selective applications of these analogues as antiviral/antitumor drugs.
Nucleos(t)ide analogues (NA) belong to a family of compounds widely used in anticancer/antiviral treatments. They generally exhibit a cell toxicity limited by cellular uptake levels and the resulting nucleos(t)ides metabolism modifications, interfering with the cell machinery for nucleic acids synthesis. We previously synthesized purine nucleos(t)ide analogues N7-coordinated to a platinum centre with unaltered sugar moieties of the type: [Pt(dien) (N7-dGuo)](2+) (1; dien = diethylenetriamine; dGuo = 2'-deoxy-guanosine), [Pt(dien)(N7-dGMP)] (2; dGMP = 5'-(2'-deoxy)-guanosine monophosphate), and [Pt(dien)(N7-dGTP)]2-(3; dGTP = 5'-(2'-deoxy)-guanosine triphosphate), where the indicated electric charge is calculated at physiological pH (7.4). In this work, we specifically investigated the uptake of these complexes (1-3) at the plasma membrane level. Specific experiments on HeLa cervical cancer cells indicated a relevant cellular uptake of the model platinated deoxynucleos(t)ide 1 and 3 while complex 2 appeared unable to cross the cell plasma membrane. Obtained data buttress an uptake mechanism involving Na+-dependent concentrative transporters localized at the plasma membrane level. Consistently, 1 and 3 showed higher cytotoxicity with respect to complex 2 also suggesting selective possible applications as antiviral/antitumor drugs among the used model compounds.
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