Gold(III) complexes with thiosemicarbazonate ligands as potential anticancer agents: Cytotoxicity and interactions with biomolecular targets

Author(s):Show less -

Possato, Bruna ^[1] ; Dalmolin, Luciana Falcco ^[1] ; Pereira, Luiz Miguel ^[1] ; Alves, Jacqueline Querino ^[2] ; Silva, Raphael Tristao Cruvinel ^[3] ; Gelamo, Rogerio Valentim ^[4] ; Yatsuda, Ana Patricia ^[1] ; Lopez, Renata Fonseca Vianna ^[1] ; de Albuquerque, Sergio ^[1] ; Leite, Natalia Bueno ^[3] ; Maia, Pedro Ivo da Silva ^[3]

Affiliation

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Ribeirao Preto - Brazil

^[2] Prefeitura Municipal Ribeirao Preto, Secretaria Educ, Ribeirao Preto - Brazil

^[3] Univ Fed Triangulo Mineiro, Nucl Desenvolvimento Compostos Bioat NDCBio, Uberaba - Brazil

^[4] Univ Fed Triangulo Mineiro, Inst Ciencias Tecnol & Exatas, Uberaba - Brazil

• Document type: Journal article
• Source: European Journal of Pharmaceutical Sciences; v. 162, JUL 1 2021.
• Web of Science Citations: 0

Abstract

Gold(III) complexes have been studied for the past years due to their anticancer properties and great affinity to biotargets, such as enzymes and proteins, which support their pharmacological applications. Within this scope, in this work the antiproliferative activities of two Au(III)-thiosemicarbazonate complexes, {[}AuClL1] (1, L1: (E,Z)-Nethyl-N'-(3-nitroso-kN)butan-2-ylidene)carbamohydrazonothioato-k2 N2,S) and {[}Au(Hdamp)L2]Cl (2, L2: N-(N{''}, N{''}-diethylaminothiocarbonyl)-N'(N{''}', N{''}'-dimethylcarbothioamide)benzamidineto-kN,k2S and Hdamp: 2-(N, N-dimethylaminomethyl)-phenyl-C1), and their affinities to possible biological targets were investigated. Three different tumor cell lines were used to perform the cytotoxicity assays, including one cisplatin-resistant model, and the results showed lower EC50 for 1 over 2 in every case: B16F10 (4.1 mu M and 15.6 mu M), A431 (4.0 mu M and >50 mu M) and OVCAR3 (4.2 mu M and 24.5 mu M). However, a lower toxicity to fibroblast 3T3 cell line was observed for 2 (30.58 mu M) when compared to 1 (7.17 mu M), resulting in comparable therapeutic indexes. Both complexes presented strong affinity to HSA: they distorted the secondary structure of the protein, as verified by circular dichroism, but 1 additionally presented the apparent fluorescence quenching constant (Kapp) ten times greater than 2, which was probably due to the fact of 1 being able to denature HSA. The ethidium bromide displacement assay showed that neither 1 nor 2 are strong DNA intercalators, which is in agreement with what was observed through the UV-vis titration. In both cases, the 260 nm band presented hyperchromism, which can indicate ionic interactions or DNA damage. In fact, 1 was able to damage the pGEM plasmid, similarly to cisplatin, as verified by agarose gel electrophoresis and Atomic Force Microscopy. Biophysical studies in cancer cells model membranes were also performed in order to investigate the interaction of the gold complexes to lipid bilayers and revealed that the compounds interact with the membranes by exhibiting partition coefficients of 103 order of magnitude. Overall, both complexes were found to be promising candidates for the development of a future anticancer drug against low sensitive or cisplatin resistant tumors. (AU)

• FAPESP's process: 18/21020-3 - Actin-depolymerization factor (NcADF): oxidation as regulator of NcADF activity on programmed cell death of Neospora caninum
• Grantee: Ana Patricia Yatsuda Natsui
• Support type: Regular Research Grants
• FAPESP's process: 18/10711-5 - Evaluation of the potential of phenothiazinium dyes for Toxoplasma gondii control
• Grantee: Luiz Miguel Pereira
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 18/24544-3 - Evaluation of metal complexes coordinated to melatonin derivatives as metal-drug candidates: synthesis, characterization and studies of trypanocidal activity
• Grantee: Sérgio de Albuquerque
• Support type: Regular Research Grants