Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume -, Issue -, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202301078
Keywords
anticancer agents; C-H activation; organometallic nucleosides; platinum complexes; reductive stress
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Platinum(II) complexes with N-heterocyclic carbenes based on guanosine and caffeine were synthesized by unassisted C-H oxidative addition, leading to the corresponding trans-hydride complexes. Platinum guanosine derivatives with triflate or bromide were also synthesized for structure-activity correlation. The hydride compounds showed high antiproliferative activity against all tested cell lines and changing the counterion had no significant effect. Increasing the bulkiness at N7 maintained the antiproliferative activity while decreasing toxicity for non-cancer cells.
Platinum(II) complexes bearing N-heterocyclic carbenes based guanosine and caffeine have been synthesized by unassisted C-H oxidative addition, leading to the corresponding trans-hydride complexes. Platinum guanosine derivatives bearing triflate as counterion or bromide instead of hydride as co-ligand were also synthesized to facilitate correlation between structure and activity. The hydride compounds show high antiproliferative activity against all cell lines (TC-71, MV-4-11, U-937 and A-172). Methyl Guanosine complex 3, bearing a hydride ligand, is up to 30 times more active than compound 4, with a bromide in the same position. Changing the counterion has no significant effect in antiproliferative activity. Increasing bulkiness at N7, with an isopropyl group (compound 6), allows to maintain the antiproliferative activity while decreasing toxicity for non-cancer cells. Compound 6 leads to an increase in endoplasmic reticulum and autophagy markers on TC71 and MV-4-11 cancer cells, induces reductive stress and increases glutathione levels in cancer cells but not in non-cancer cell line HEK-293.
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