During the last 30 years, Ru, Ir, Pd, Fe or Cu have appeared as promising alternatives to overcome the drawbacks encountered with Pt anticancer compounds. Beyond all of them, and mainly during the last decade, Cu complexes have awakened strong interest as therapeutic agents. Two features make Cu attractive to be used in chemotherapy: its nature as an endogenous metal —which may imply fewer side effects than other exogenous metals- and its Cu(II)/Cu(I) redox pair —which can promote reactive oxygen species (ROS) generation. The production of ROS is not only reported to cause cellular damage, but also to offer a putative discrimination between healthy and non-healthy cells. On the first part of this thesis work, we report the synthesis, characterization and biological evaluation of a dimeric Cu(II) complex bearing a N,O-donor salphen-like ligand ((E)-N-(2-(2-hydroxybenzylideneamino)phenyl)acetamide, L1) specifically designed to promote a fast Cu(II)/Cu(I) redox interconversion. In vitro assays outline the high potentiality of the complex to undergo ROS generation inside HeLa cells, and that it shows higher cytotoxicity in cancer than in normal cell lines. Besides, its interactions with some proteins have also been tested, showing that the formed protein-complex adducts do not represent any loss of biological activity respect to the complex itself. From this promising starting point, the Cu(II) complex of L1 ([Cu(L1)]2) serves as the backbone for the synthesis of two -chloro and -bromo analogs. The presence of electrowithdrawing groups intend to tune the redox behavior of the corresponding Cu(II) complexes, and concomitantly, their ROS generation capabilities. However, one of the main drawbacks faced with these two halogen-derived complexes was their poor solubility and bioavailability. Therefore, several functionalization strategies have been explored to overcome it. The first strategy aimed at increasing the solubility while maintaining the same Cu(II) coordination environment, i.e., the high redox activity observed for the initial [Cu(L1)]2 complex. In light of this, a sulfonate group and an Arginine residue have been selected based on their pKa and biological relevance. Secondly, and in order to enhance the delivery of the complex and the candidacy as future anticancer drug, specific improvement on the cellular uptake -ergo, on the cytotoxicity- has been attained by derivatizing [Cu(L1)]2 with two specific Arginine-rich Cell-Penetrating Peptides. Finally, the last part of our work opens the gate to the use of a versatile multimodal dendritic platform as a promising drug carrier. Its potentiality in drug delivery and its copper coordination capabilities have been thoroughly demonstrated. The conjugation approach of the [Cu(L1)]2 complex to the platform is also reported as a proof-of-concept of the versatility of this system for future tailor-made anticancer targeted therapies.
Novel Cu(II) complexes bearing N,O-donor heteroaromatic ligands as potential anticancer drugs. A redox-active metallic core.
Peña Aparicio, J. (Author). 13 Dec 2019
Student thesis: Doctoral thesis
Student thesis: Doctoral thesis