Development of novel anticancer agents for protein targets

Natalia Estrada Ortiz

Research output: ThesisThesis fully internal (DIV)

906 Downloads (Pure)

Abstract

The research described in this thesis was aimed to discover and evaluate new anticancer drugs. Two different approaches were undertaken. In the first part, the design and evaluation of new p53-MDM2/X inhibitors based on previously described compounds are presented, in an attempt to increase their potency and explore different regions of the p53-MDM2/X interphase. Synthetic macrocycles and Bis(1'h-indole) heterocycles were synthesized as potent inhibitors of the p53/MDM2 interaction with affinity towards MDM2 in the low micromolar range. In the second part, another class of compounds, metal complexes, were synthetized aiming to interact with several protein targets and act as anticancer agents. Several series of metal complexes were studied to determine their potential cytotoxic activity against cancer cell lines and to unravel their possible mechanism of action compared to known metal containing drugs such as cisplatin and auranofin. Furthermore, evaluation of their toxicity was performed in healthy tissue using rat Precision Cut Tissue Slices (PCTS) to unravel uptake, pathways involved in the toxicity and possible selectivity of the compounds towards cancer cells. The three families of gold complexes evaluated presented a different toxicity profile compared to known metal containing drugs, including variations in the target cells, uptake and mechanisms of toxicity in cancer cells and healthy tissue
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University of Groningen
Supervisors/Advisors
  • Dömling, Alex, Supervisor
  • Casini, Angela, Supervisor
  • Groothuis, Geny, Supervisor
Award date20-Oct-2017
Place of Publication[Groningen]
Publisher
Print ISBNs978-94-034-0142-3
Electronic ISBNs978-94-034-0141-6
Publication statusPublished - 2017

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