Design and development of a new ruthenium metallodrug candidate with synergistic ligands

Author(s)

Renan Ribeiro Bertoloni

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-08-23

Examining board members

Sofia Nikolaou; Alzir Azevedo Batista; Roberto Santana da Silva

• Advisor: Sofia Nikolaou

Abstract

This work consists of the synthesis, characterization and verification of some biological properties of a series of three coordination complexes with the general formula [Ru(tpy)(dppz)L]n+, where tpy = 2,2\':6\',2\'\'-terpyridine, dppz = dipyrido-[3,2-a:2\',3\'-c]- phenazine and L = Cl- (n = 1), H2O (n = 2) or NO2 (n = 1). Initially, the work proposed to synthesize the new compound [Ru(tpy)(dppz)NO]3+, but due to the low electronic density of the metallic center, proven through experiments and in silico calculations, this compound was unstable and the work was carried out using the substitute [Ru(tpy)(dppz)NO2] + , also new in the literature. This compound presents the same biological potentials as the previous one, namely the ability to generate 1O2, intercalation with DNA and photorelease of NO. The series was synthesized and characterized using UV-Vis absorption spectroscopy, emission spectroscopy, time-resolved absorption spectroscopy, vibrational spectroscopy and NMR spectroscopy. All the studied compounds were able to generate 1O2 and the compound [Ru(tpy)(dppz)NO2] + presented the highest quantum yield of generation. It was demonstrated that all compounds interact relatively strongly with HSA and DNA, and both interactions were verified by the Stern-Volmer method and, in the case of HSA, molecular docking calculations. The interaction with DNA was determined to be intercalation by circular dichroism spectroscopy, DNA melting temperature measurements and molecular docking. The compound [Ru(tpy)(dppz)NO2] + was able to release NO upon irradiation, and this release generated a cytoprotective effect in healthy cells verified in an in vitro study with tumor and non-tumor lung cells. All compounds were selectively mildly cytotoxic to tumor cells. The analysis of all the results shows that this system is promising for the design of new metallopharmaceuticals, in a way that slight alterations in the structure of the ligands may generate changes in the electronic structure of the compounds that make them capable of returning even more promising results for medicinal inorganic chemistry. (AU)

• FAPESP's process: 20/15607-1 - Synthesis, characterization and biological properties of a photosensitizing ruthenium mononuclear complex with a bulky ligand and a DNA intercalator with photoinduced release of NO
• Grantee: Renan Ribeiro Bertoloni
• Support Opportunities: Scholarships in Brazil - Master