abstract
DNA chains with sequential guanine (G) repeats can lead to the formation of G-quadruplexes (G4), which are found in functional DNA and RNA regions like telomeres and oncogene promoters. The development of molecules with adequate structural features to selectively stabilize G4 structures can counteract cell immortality, highly described for cancer cells, and also downregulate transcription events underlying cell apoptosis and/or senescence processes. We describe here, the efficiency of four highly charged porphyrins-phosphonium conjugates to act as G4 stabilizing agents. The spectrophotometric results allowed to select the conjugates P2-PPh3 and P3-PPh3 as the most promising ones to stabilize selectively G4 structures. Molecular dynamics simulation experiments were performed and support the preferential binding of P2-PPh3 namely to MYC and of P3-PPh3 to KRAS. The ability of both ligands to block the activity of Taq polymerase was confirmed and also their higher cytotoxicity against the two melanoma cell lines A375 and SK-MEL-28 than to immortalized skin keratinocytes. Both ligands present efficient cellular uptake, nuclear co-localization and high ability to generate 1O2 namely when interacting with G4 structure. The obtained data points the synthesized porphyrins as promising ligands to be used in a dual approach that can combine G4 stabilization and Photodynamic therapy (PDT).
keywords
AMBER FORCE-FIELD; C-MYC; MOLECULAR-DYNAMICS; GRAPHENE OXIDE; NUCLEIC-ACIDS; ALAMAR BLUE; HUMAN SKIN; DNA; PROMOTER; STABILIZATION
subject category
Biochemistry & Molecular Biology; Chemistry; Polymer Science
authors
Moura, NMM; Guedes, S; Salvador, D; Oliveira, H; Alves, MQ; Paradis, N; Wu, C; Neves, MGPMS; Ramos, CIV
our authors
Helena Oliveira
Post-Doc FellowshipGroups
acknowledgements
This work received financial support from FCT/MCTES(UIDP/50006/2020 DOI 10.54499/UIDP/50006/2020) through national funds and the FCT project PORP2PS (EXPL/QUI-QOR/0586/2021).NMM Moura and CIV Ramos thanks FCT for funding through program DL 57/2016-Norma transitoria (CDL-CTTRI-048-88-ARH/2018 and CDL-CTTRI-047-88-ARH/2018). D. Salvador thanks FCT for the PhD grant (2022.11049.BD).