Doctoral Themes - Proposals
Novel nucleoside-ruthenium cyclopentadienyl conjugates for cancer therapy
Supervisors
Nuno Manuel Xavier, nmxavier@fc.ul.pt
Tânia S. Morais, tsmorais@fc.ul.pt
Registration Institution
Faculdade de Ciências (Universidade de Lisboa)
Project description
Nucleoside analogues (NAs) have great relevance in medicinal chemistry, due to their ability to inhibit/interfere in biological processes in which their natural analogues play an essential role, e.g. cell division, nucleic acid biosynthesis or cell signalling[1]. Gemcitabine and fludarabine NAs are widely used as anti-cancer agents in clinics. However, NAs therapeutic use is often limited by their low bioavailability, low selectivity, and chemotherapeutic resistance. Nucleoside transport is a key process that helps maintain the hyperproliferative state of most cancer cells. Therefore, NAs can constitute also important vectors for targeted therapy since they may mimic their natural analogues in cellular membrane privileged passage through nucleoside transporters.
Research on metal-based drugs has made remarkable progress in cancer therapy. Great attention has been paid to ruthenium compounds due to their high cytotoxicity to cancer cells, low toxicity, and lower drug resistance. We have been successful exploring the use of Ru(II)-cyclopentadienyl-based compounds as prospective anticancer agents for cancers without clinical cure[2-4].
The main goal of this project is the development of new Ru(II)-cyclopentadienyl-nucleoside conjugates (RuNAs) and their use as potential targeted anticancer agents. When nucleosides are attached to metal-complexes new interesting properties can be achieved making them more reactive to their surroundings creating innovative action mechanisms. The strategy is creating a synergistic effect by the coordination of Ru-organometallic complexes and nucleoside motifs already known for their high in vitro/in vivo efficiency against cancer[2-6], aiming at improving their selectivity, and pharmacokinetic performance (metabolic rate, physicochemical properties, or binding affinities). This proposal brings together the consolidated and recognized experience in organic and organometallic chemistry of two CQE-research groups (HC e BIOIN).
References
[1] L. P. Jordheim et. al, Nat. Rev. Drug. Discov. 2013, 12, 447-464.
[2] J. F. Machado et.al, Dalton Trans., 2020, 49, 5974-5987.
[3] N. Mendes et.al, Anti-Cancer Agents Med. Chem., 2017, 17, 126 - 136.
[4] T. S. Morais et.al, Future Med. Chem., 2016, 8, 527-544.
[5] N. M. Xavier et al, Org. Biomol. Chem., 2017, 15, 4667-4680.
[6] N. M. Xavier, et. al., Pure Appl. Chem. 2019, 91, 1085-1105.
Keywords
Nucleoside analogues; Ru(II)-cyclopentadienyl-based compounds; metal-nucleoside conjugates; cancer therapy
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