Polydentate imine ligands as modulators of copper reactivity in inflammation-related diseases and in bioorthogonal coupling reactions

• Grant number: 18/21537-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): January 01, 2019
• Effective date (End): August 31, 2021
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Ana Maria da Costa Ferreira
• Grantee: Raphael Enoque Ferraz de Paiva
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID

Abstract

In this project we will develop polydentate imine-derived ligands containing oxindole, imidazole and triazole moieties for stabilization of copper in both of its usual oxidation states in biological systems. These ligands will be investigated for two complementary applications. In one front, the polydentate ligands will be used for the synthesis of copper(II) metallodrugs aimed at the treatment of inflammation-related diseases. Copper has a central but dichotomic role related to inflammatory processes, involving reactive oxygen and/or nitrogen reactive species, as it has both pro- and anti-inflammatory properties. Furthermore, the correlation between cancer development and inflammation has become more and more clear, with a key aspect being the role of reactive oxygen and nitrogen species. That prompts us to investigate the fundamental role of copper in both processes. Based on our previous experience in studies of copper ion reactivity in biological medium, we intend to go further in our investigations on the possible mechanisms of action of potential antitumor agents based on copper, focusing on the link between cancer and inflammatory processes. Additionally, we intend to use the the polydentate imine-derived ligands as alternative co-ligands in the "click" copper(I)-catalyzed alcino-azide cycloaddition. Under the scope of Bioorthogonal Catalysis (catalysis in biological media), we aim at obtaining triazole-derived compounds with anticancer and fluorescent properties directly in aqueous media. Once these reactions are optimized, they can be translated to in cellulo and in vivo applications.

Scientific publications

(10)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE PAIVA, RAPHAEL E. F.; NETO, ANTONIO MARCAL; SANTOS, IGOR A.; JARDIM, ANA C. G.; CORBI, PEDRO P.; BERGAMINI, FERNANDO R. G.. What is holding back the development of antiviral metallodrugs? A literature overview and implications for SARS-CoV-2 therapeutics and future viral outbreaks. DALTON TRANSACTIONS, v. 49, n. 45, p. 16004-16033, DEC 7 2020. (18/12062-4, 18/21537-6)

DE PAIVA, RAPHAEL E. F.; PETERSON, ERICA J.; DU, ZHIFENG; FARRELL, NICHOLAS P.. The leaving group in Au(I)-phosphine compounds dictates cytotoxic pathways in CEM leukemia cells and reactivity towards a Cys(2)His(2) model zinc finger. DALTON TRANSACTIONS, v. 49, n. 45, p. 16319-16328, DEC 7 2020. (18/21537-6)

NAKAHATA, DOUGLAS H.; DE PAIVA, RAPHAEL E. F.; LUSTRI, WILTON R.; CORBI, PEDRO P.. Sulfonamide-containing copper(ii) complexes: new insights on biophysical interactions and antibacterial activities. NEW JOURNAL OF CHEMISTRY, v. 44, n. 40, p. 9-pg., 2020-10-28. (15/09833-0, 15/20882-3, 18/12062-4, 18/21537-6, 18/12590-0, 15/25114-4)

SANTOS, IGOR ANDRADE; DOS SANTOS PEREIRA, ANNA KARLA; GUEVARA-VEGA, MARCO; FERRAZ DE PAIVA, RAPHAEL ENOQUE; SABINO-SILVA, ROBINSON; BERGAMINI, FERNANDO R. G.; CORBI, PEDRO P.; JARDIM, ANA CAROLINA G.. Repurposing potential of rimantadine hydrochloride and development of a promising platinum(II)-rimantadine metallodrug for the treatment of Chikungunya virus infection. Acta Tropica, v. 227, p. 12-pg., 2022-03-01. (18/21537-6, 18/12062-4)

MARTINS, DANIEL OLIVEIRA SILVA; SOUZA, RAFAEL APARECIDO CARVALHO; FREIRE, MARJORIE CAROLINE LIBERATO CAVALCANTI; DE MORAES ROSO MESQUITA, NATHALYA CRISTINA; SANTOS, IGOR ANDRADE; DE OLIVEIRA, DEBORA MORAES; NICOLAU JUNIOR, NILSON; DE PAIVA, RAPHAEL ENOQUE FERRAZ; HARRIS, MARK; OLIVEIRA, CAROLINA GONCALVES; et al. Insights into the role of the cobalt(III)-thiosemicarbazone complex as a potential inhibitor of the Chikungunya virus nsP4. JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY, v. 28, n. 1, p. 15-pg., 2022-12-09. (18/21537-6)

FERRAZ DE PAIVA, RAPHAEL ENOQUE; VIEIRA, EDUARDO GUIMARAES; RODRIGUES DA SILVA, DANIEL; WEGERMANN, CAMILA ANCHAU; COSTA FERREIRA, ANA MARIA. Anticancer Compounds Based on Isatin-Derivatives: Strategies to Ameliorate Selectivity and Efficiency. FRONTIERS IN MOLECULAR BIOSCIENCES, v. 7, FEB 4 2021. (13/07937-8, 16/16735-8, 18/21537-6)

FAZZI, RODRIGO B.; FERRAZ DE PAIVA, RAPHAEL E.; DA COSTA FERREIRA, ANA M.. A combined EPR spectroscopy and DFT-based structural interpretation of the antitumor properties of oxindolimine-copper(II) complexes. ARKIVOC, n. 2, p. 123-133, 2020. (11/50318-1, 13/07937-8, 18/21537-6)

ABRAO, FARIZA; SILVA, THAYNA SOUZA; MOURA, CLAUDIA L.; AMBROSIO, SERGIO RICARDO; SOLA VENEZIANI, RODRIGO CASSIO; DE PAIVA, RAPHAEL E. F.; BASTOS, JAIRO KENUPP; GOMES MARTINS, CARLOS HENRIQUE. Oleoresins and naturally occurring compounds of Copaifera genus as antibacterial and antivirulence agents against periodontal pathogens. SCIENTIFIC REPORTS, v. 11, n. 1, MAR 2 2021. (18/21537-6, 16/23012-2, 11/13630-7)

MANZANO, CARLOS M.; NAKAHATA, DOUGLAS H.; DE PAIVA, RAPHAEL E. F.. Revisiting metallodrugs for the treatment of skin cancers. Coordination Chemistry Reviews, v. 462, p. 71-pg., 2022-03-19. (18/21537-6, 17/25995-6)

FAZZI, RODRIGO B.; FERRAZ DE PAIVA, RAPHAEL E.; DA COSTA FERREIRA, ANA M.. A combined EPR spectroscopy and DFT-based structural interpretation of the antitumor properties of oxindolimine-copper(II) complexes. ARKIVOC, v. N/A, p. 11-pg., 2020-01-01. (11/50318-1, 18/21537-6, 13/07937-8)