Applied Molecular Biosciences Unit

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Antimicrobial and antitumor activity of S-methyl dithiocarbazate Schiff base zinc(II) complexes

Publication . Gomes, Filipa Ramilo; Addis, Yemataw; Tekamo, Israel; Cavaco, Isabel; Campos, Débora L.; Pavan, Fernando R.; Gomes, Clara S.B.; Brito, Vanessa; Santos, Adriana O.; Domingues, F.C.; Luís, Ângelo; Marques, M. Matilde; Pessoa, João Costa; Ferreira, Susana; Silvestre, Samuel; Correia, Isabel

Schiff bases (SB) obtained from S-methyl dithiocarbazate and aromatic aldehydes: salicylaldehyde (H2L1), o-vanillin (H2L2), pyridoxal (H2L3) and 2,6-diformyl-4-methylphenol (H3L4), and their corresponding Zn(II)-complexes (1-4), are synthesized. All compounds are characterized by elemental analyses, infrared, UV-Vis, nuclear magnetic resonance spectroscopy and mass spectrometry. The structures of H2L2 and [Zn2(L1)2(H2O)(DMF)] (1a) (DMF = dimethylformamide) are solved by single crystal X-ray diffraction. The SB coordinates the metal center through the Ophenolate, Nimine and Sthiolate atoms. The radical scavenging activity is tested using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, with all ligand precursors showing IC50 values ~40 μM. Cytotoxicity studies with several tumor cell lines (PC-3, MCF-7 and Caco-2) as well as a non-tumoral cell line (NHDF) are reported. Interestingly, 1 has relevant and selective antiproliferative effect against Caco-2 cells (IC50 = 9.1 μM). Their antimicrobial activity is evaluated in five bacterial strains (Klebsiella pneumoniae, Acinetobacter baumannii, Listeria monocytogenes, Pseudomonas aeruginosa and Staphylococcus aureus) and two yeast strains (Candida albicans and Candida tropicalis) with some compounds showing bacteriostatic and fungicidal activity. The minimal inhibitory concentration (MIC90) of HnL against Mycobacterium tuberculosis is also reported, with H2L2 and H3L4 showing very high activity (MIC90 < 0.6 μg/mL). The ability of the compounds to bind bovine serum albumin (BSA) and DNA is evaluated for H3L4 and [Zn2(L4)(CH3COO)] (4), both showing high binding constants to BSA (ca. 106 M-1) and ability to bind DNA. Overall, the reported compounds show relevant antitumor and antimicrobial properties, our data indicating they may be promising compounds in several fields of medicinal chemistry.

2021Journal article

Restricted access

Promoter Demethylation Upregulates STEAP1 Gene Expression in Human Prostate Cancer: In Vitro and In Silico Analysis

Publication . Rocha, Sandra; Sousa, Inês; Gomes, Inês M.; Arinto, Patrícia; Pinheiro, Pedro Costa; Coutinho, Eduarda; Santos, Cecilia; Jerónimo, Carmen; Lemos, Manuel C.; Passarinha, L A; Socorro, Sílvia; Baptista, Cláudio Maia

The Six Transmembrane Epithelial Antigen of the Prostate (STEAP1) is an oncogene overexpressed in several human tumors, particularly in prostate cancer (PCa). However, the mechanisms involved in its overexpression remain unknown. It is well known that epigenetic modifications may result in abnormal gene expression patterns, contributing to tumor initiation and progression. Therefore, this study aimed to analyze the methylation pattern of the STEAP1 gene in PCa versus non-neoplastic cells. Bisulfite amplicon sequencing of the CpG island at the STEAP1 gene promoter showed a higher methylation level in non-neoplastic PNT1A prostate cells than in human PCa samples. Bioinformatic analysis of the GEO datasets also showed the STEAP1 gene promoter as being demethylated in human PCa, and a negative association with STEAP1 mRNA expression was observed. These results are supported by the treatment of non-neoplastic PNT1A cells with DNMT and HDAC inhibitors, which induced a significant increase in STEAP1 mRNA expression. In addition, the involvement of HDAC in the regulation of STEAP1 mRNA expression was corroborated by a negative association between STEAP1 mRNA expression and HDAC4,5,7 and 9 in human PCa. In conclusion, our work indicates that STEAP1 overexpression in PCa can be driven by the hypomethylation of STEAP1 gene promoter.

2021Journal article

Open access