Doctoral Themes

Multifunctional Ruthenium and Selenium Drugs to Overcome Multidrug Resistance in Cancer

Supervisors

Andreia Valente, amvalente@fc.ul.pt

Alexandra Antunes, alexandra.antunes@tecnico.ulisboa.pt

Registration Institution

Faculdade de Ciências, Universidade de Lisboa

Project description

Cancer is the second leading cause of death worldwide. A severe limitation to the efficacy of the drugs in clinical use for the treatment of this disease is multidrug resistance (MDR), where P-gp and MRP1 (membrane transport proteins) play a key role in pumping drugs out of cells. Our preliminary results identified ruthenium organometallic compounds as potent cytotoxic agents and as P-gp and MRP-1 inhibitors, particularly in cancer cell lines resistant to the drugs in clinical use.[1-2] Yet, anticancer drug resistance can arise from a multitude of underlying mechanisms. In that frame, we have also disclosed organoselenium derivatives able to overcome this issue, which display activity towards key antioxidant targets.[3,4]

Effective fight against MDR requires a multidimensional approach and molecular hybridization, by combining two pharmacophoric units, arises as a promising strategy. Therefore, within this Ph.D. project, we will develop new multifunctional ruthenium organometallic compounds bearing organoselenium-based ligands as multidrug resistance reversing agents.

This multidisciplinary project offers an excellent formation not only in organic and organometallic synthesis (and compounds’ purification) using Schlenk, but also in assays to assess ADME properties of Hit compounds as well as in several characterization techniques, such as FTIR, NMR, UV-Vis. and MS. In addition, the student will be in a six-month scientific mission to Torino University in the frame of MDR-based studies.

If successful, this Ph.D. will be a very important contribution to the field of cancer MDR, not only in terms of fundamental science, but also as a real possibility to fight several untreatable cancers.

References: [1] L. Côrte-Real et al. Eur. J. Med. Chem., 2019, https://doi.org/10.1016/j.ejmech.2018.12.022 [2] R. Teixeira et al. Inorg. Chem. Front., 2021, https://doi.org/10.1039/D0QI01344G [3] I. L. Martins et al. J. Med. Chem. 2015, https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00230 [4] I. Santos et al. Nutrients. 2019, 11,2523 https://doi.org/10.3390/nu11102523

Keywords

Multidrug resistance; ruthenium; Selenium; Molecular hybridization; Multifunctional drugs

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