Metal complexes of Ag(I) and Pt(II) with uracil derivatives: synthesis, characterization, evaluation of antiproliferative activities on human tumor cells, and determination of the main cellular targets.

• Grant number: 24/18107-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2025
• End date: November 30, 2028
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Pedro Paulo Corbi
• Grantee: Anna Karla dos Santos Pereira
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The emergence of a large number of new cases, as well as cellular resistance to multiple drugs, have been a challenge in the fight against several types of cancer. One of the strategies to overcome this challenge is the development of new drugs that combine drugs currently available in the clinic (or under clinical tests) and metals with recognized cytotoxic activities. Uracil derivatives are widely known for their recognized antiproliferative activity on tumor cells and for their potential to cure skin lesions. When associated with metals such as the Pt(II) ion, which has recognized application in the synthesis of antineoplastic drugs, an important line of research emerges for the production of new anticancer agents. This approach is part of the CEPID/FAPESP CancerThera project, which aims to develop drugs for cancer therapy and diagnosis. This project, which began just over a year ago, combines basic and clinical research in a model that is unusual in Brazil. This project is composed by researchers from the areas of Chemistry, Pharmacy and Medicine from UNICAMP (host institution), the University of São Paulo-USP and the School of Medical Sciences of Santa Casa de São Paulo.In this context, the objectives of this project are the synthesis, characterization and study of the antiproliferative activities of new metal complexes of Ag(I) and Pt(II) with uracil derivatives, including determination of potential cellular targets. The complexes will be synthesized in aqueous solutions and characterized by a set of chemical and spectroscopic analyses. The in vitro cytotoxic studies on different cell types, with emphasis on skin tumors, will be performed using colorimetric methods to determine IC50 values (concentration that inhibits 50% of cell growth or cytostatic effect), and the obtained values will be compared with those from chemotherapeutic agents such as cisplatin and 5-fluorouracil to determine the efficacy and therapeutic potential of the complexes. Studies on cellular targets will be performed based on the interaction of the compounds with model amino acids (N-acetyl-L-tryptophan and others), with proteins and enzymes such as albumin, lysozyme, and DNA methyltransferases, and with DNA. An in vivo animal study model will be designed and submitted to CEP/UNICAMP for those drug candidates that show the most promising results considering the in vitro studies based on the group's previous experience. (AU)