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Synthesis, characterization and determination of antimicobacterial and antitumoral activities of Ag(I), Au(I), Pd(II) e Pt(II) complexes with sweeteners and derivatives

Grant number: 05/00174-2
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): July 01, 2005
Effective date (End): January 31, 2008
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Antonio Carlos Massabni
Grantee:Mauricio Cavicchioli
Home Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil


Inorganic complexes have been used in Medicine for treatment of several diseases such as cancer, arthritis and bacterial infections. Palladium and platinum complexes are used in cancer chemotherapy. Cisplatin, cis-[PtCl2(NH3)2], discovered by Barnet Rosenberg in 1965, is the most widely used inorganic complex in Medicine and it was the first complex used in cancer chemotherapy. Its mechanism of action basically involves binding to DNA of tumor cells, inhibiting replication and transcription. Cisplatin is effective against ovarian, testicular, colon and cervical tumors. In testicular cancer treatment, it has a greater than 90% cure rate. Au(I) complexes, such as auranofin, are clinically used for rheumatoid arthritis treatment and Ag(I) complexes have antibacterial effects. Silver sulphadiazine is topically used to prevent bacterial infections in severe burns. However, these compounds have some disadvantages as high manufacture cost, low solubility, increased drug resistance and side effects, specially neurological and renal disturbance (due to toxic phosphines as ligands). As an example, cisplatin, despite of the success of the clinical treatment, has its total effectiveness limited by side effects (neurological and renal disturbance) and acquired and intrinsic drug resistance. Resistance is consequences of cellular repairing mechanisms by nucleotide excision repair (NER) reactions which remove DNA-cisplatin adducts and repair DNA, allowing normal cell replication and transcription. So, it is important the discovery of new compounds active against a wider spectrum of tumors and which present less side-effects. A strategy found in more recent researches is the synthesis and design of structure of novel platinum complexes, in order to make possible new modes of DNA binding and, consequently, to inhibit repairing cellular mechanisms. Ligands with low manufacture costs, low toxicity and high affinity to the metals broached in this project ((Pt(II), Pd(II), Au(I) e Ag(I)) are ideal to be applied in Inorganic Medicinal Chemistry. Sweeteners, as aspartame, saccharin, cyclamate, (+-)-2-(p-methoxiphenoxi)propionic acid and acesulfame-K present these characteristics and could be used as ligands for synthesis of medicinal inorganic complexes. Some esters derived from sweeteners could also be used as neutral ligands. The aim of this project is synthesis, characterization and study of antitumoral and antimycobacterial activities of inorganic complexes of Ag(I), Au(I), Pd(II) and Pt(II) using sweeteners molecules (or derived from sweeteners) as ligands. After characterization, biological essays will be carried out with Ag(I) complexes in order to determine the minimal inhibitory concentration (MIC) of the drug necessary to inhibit 99% of mycobacterial grow-up. The species of bacteria to be studied are: Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium malmoense and Mycobacterium kansasii. In vitro and in vivo biological essays with Pt(II) e Pd(II) complexes will also be carried out in order to measure their antiproliferative and citotoxic activity against tumor cells of a variety of human cancer. Moreover, we intend to work, during the post-doctoral course, in Prof. Farrell’s laboratory, in “Virginia Commonwealth University" -USA-, which has ideal infrastructure for studies about antitumoral complexes and, studies about their mechanisms of action on DNA. The learned techniques will be applied in the studies which are developed in Brazil. (AU)

Scientific publications
(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)
CAVICCHIOLI, MAURICIO; MASSABNI, ANTONIO C.; HEINRICH, TASSIELE A.; COSTA-NETO, CLAUDIO M.; ABRAO, EMILIANA P.; FONSECA, BENEDITO A. L.; CASTELLANO, EDUARDO E.; CORBI, PEDRO P.; LUSTRI, WILTON R.; LEITE, CLARICE Q. F. Pt(II) and Ag(I) complexes with acesulfame: Crystal structure and a study of their antitumoral, antimicrobial and antiviral activities. Journal of Inorganic Biochemistry, v. 104, n. 5, p. 533-540, MAY 2010. Web of Science Citations: 41.

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