Peptide conjugates containing chlorambucil or tetradentate aminopyridine ligands for anticancer treatment

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Nowadays, the search for new drugs against cancer is one of the major goals to improve the quality of life of patients. The development of more selective treatments against cancer cells may lead to a significant reduction of the side-effects, being one of the most important topics in current research. In this regard, cell-penetrating peptides (CPPs) have been described to efficiently transport therapeutic molecules across the cell membrane. Furthermore, some metal complexes based on platinum (cisplatin and derivatives) are used in current chemotherapy. Despite their efficacy, these drugs display high toxicity. Thus, the design of novel complexes based on non-toxic metals (iron or manganese) is currently under way. These complexes could induce an irreversible oxidative stress through reactive oxygen species (ROS) at the subcellular level. Consequently, this might result in the alteration of the redox homeostasis and in cell death via apoptosis.The main objective of this thesis is the transport of iron or manganese complexes based on aminopyridine ligands into cancer cells through their conjugation to a non-toxic cell-penetrating peptide. Towards this aim, in one hand an undecapeptide (BP16) has been identified as a novel cell-penetrating peptide. On the other hand, it has been developed a straightforward synthetic methodology to conjugate the tetradentate aminopyridine ligands Me2PyTACN and (S,S’)-BPBP to peptide derivatives. Using this methodology, conjugates incorporating the aforementioned ligands and a tetrapeptide sequence have been prepared. These conjugates have been metallated with iron, manganese and other metals, and the resulting metallopeptides have been characterized and studied as DNA nucleases. Next, following the previous synthetic methodology, the Me2PyTACN and (S,S’)-BPBP ligands have been conjugated to the cell-penetrating peptide BP16 with the aim of being efficiently internalized into cancer cells. The resulting conjugates exhibit high cytotoxic activity similar to that observed by well-known anticancer drugs. Besides, BP16 displays high efficient drug delivery properties since it is able to enhance the uptake of the anticancer agent chlorambucil, improving its cytotoxicity against cancer cells between 6- to 10-fold. These high cytotoxic activities correlated with the high cellular uptake observed by the resulting conjugates, which it has been attributed to BP16. Based on the sum of these results, we have shown that BP16 is able to significantly enhance the cellular uptake of redox-active complexes and other well-known drugs. In brief, this study establishes that the synergy between the cytotoxic activity provided by metal complexes and their efficient transport into the cells could be useful to develop more selective therapies as well as novel anticancer treatments. ​
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