Author(s): Leitão, Maria Inês P.S. ; Turos-Cabal, Maria ; Sanchez-Sanchez, Ana Maria ; Gomes, Clara S.B. ; Herrera, Federico ; Martin, Vanesa ; Petronilho, Ana
Date: 2023
Persistent ID: http://hdl.handle.net/10362/158467
Origin: Repositório Institucional da UNL
Subject(s): anticancer agents; C−H activation; organometallic nucleosides; platinum complexes; reductive stress; Catalysis; Chemistry(all); Organic Chemistry; SDG 3 - Good Health and Well-being
Funding Information: We thank Fernanda Murtinheira for the support on the autophagy measurements. This work was supported by FCT – Fundação para a Ciência e a Tecnologia, I.P., through MOSTMICRO‐ITQB R&D Unit (UIDB/04612/2020, UIDP/04612/2020) and LS4FUTURE Associated Laboratory (LA/P/0087/2020). M.I.P.S.L. was supported by fellowships PD/BD/135483/2018 and COVID/BD/152502/2022 from FCT. A.P. acknowledges the contract CEECINST/00102/2018. The NMR spectra were acquired at CERMAX–ITQB, supported by Infrastructure Project No. 022161 (co‐financed by FEDER through COMPETE 2020, POCI, PORL and FCT through PIDDAC). C.S.B. Gomes acknowledges the XTAL – Macromolecular Crystallography group for granting access to the X‐ray diffractometer. X‐ray infrastructure financed by FCT‐MCTES through project RECI/BBBBEP/0124/2012. FH was supported by Centre grants from FCT to the BioISI Research Unit (Refs. UIDB/04046/2020 and UIDP/04046/2020) and the Microscopy facility at FCUL (as a node of the Portuguese Platform of BioImaging, reference PPBI‐POCI‐01‐0145‐FEDER‐022122), and by individual grants through FCT (Ref. PTDC/FIS‐MAC/2741/2021) and the ARSACS Foundation (Canada). Maria Turos‐Cabal was supported by fellowship from the Spanish Association Against Cancer (AECC, SV‐19‐AECC‐FPI) and the Consejería de Economía y Empleo del Principado de Asturias (FICYT, Severo‐Ochoa BP20‐073). Publisher Copyright: © 2023 Wiley-VCH GmbH.
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.
