: Thiosemicarbazones (TSCNs) constitute a broad family of compounds (R1R2C=N-NH-C(S)-NR3R4) particularly attractive because many of them display some biological activity against a wide range of microorganisms and cancer cells. Their activity can be related with their electronic and structural properties, which offer a rich set of donor atoms for metal coordination and a high electronic delocalization providing different binding modes for biomolecules. Heterocycles such as pyrrole, imidazole and triazole are present in biological molecules such as Vitamine B12 and amino acids and could potentially target multiple biological processes. Considering this, we have explored the chemistry and biological properties of thiosemicarbazones series and their complexes bearing heterocycles such as pyrrole, imidazole, thiazole and triazole. We focus at the chemistry and cytotoxicity of those derivatives to find out the structure activity relationships, and particularly we analyzed those examples with the TSCN units in which the mechanism of action information has been profoundly studied and pathways determined, to promote future studies for heterocycle derivatives.
The synthesis and characterization of three new platinum complexes, with 3,5‐diacetyl‐1,2,4‐triazole bis(4‐N‐isopropylthiosemicarbazone) as a ligand, are reported. The specific conditions under which solvent coordination takes place are reported and the X‐ray structure of the complex with one solvent molecule of dimethyl sulfoxide is resolved. Analysis of the reactivity of these platinum compounds aids in finding the best solution profile for biological investigations. Then, the interactions of the complexes with biological models, such as calf‐thymus DNA, are studied by using UV spectroscopy and tracking the changes in electrophoretic mobility produced in the supercoiled plasmid DNA model. Initial screening of these potential antitumoral compounds indicates possible selective antitumoral action.
Thiosemicarbazone moiety is a valuable scaffold for the synthesis of metallic complexes with anticancer purposes, when bearing N‐heterocyclic the final compounds possess diverse biological activities. Using thiazole as bioisosteres, the resulting thiosemicarbazones can afford synthetic drugs with a variety of pharmacological effects. Trying to elucidate, if metal complexes from α‐N‐heterocyclic thiosemicarbazones can achieve more selectivity versus special tumor lines, we have developed new metal complexes with 1H imidazole‐4‐carboxaldehyde 4 N‐p‐tolyl‐ and 4 N‐phenylthiosemicarbazone (HL1 and HL2 respectively). The solution studies of these ligands showed a tautomeric equilibria in solution and their reaction with Li2PdCl4 proved the stability of both forms affording two mononuclear Pd(II) complexes. Both tautomeric forms are clearly coordinated to palladium center acting as two different bidentate ligands. Palladium complexes’ stability in biological buffers was investigated to stablish the optimal conditions for the evaluation of cytotoxicity, that on the triple negative adenocarcinoma cell line showed IC50 values in the low micromolar range. Complexes were also studied with CT DNA (UV‐Visible spectroscopy and viscosity) and with the pBR322 plasmid supercoiled models, indicating non covalent interaction.
MAD2 is a key mitotic checkpoint protein that when overexpressed provokes chromosomal instability in gastric cancer. In this work, we used in silico analysis in combination with in vitro studies and clinical data to explore if miRNAs can regulate MAD2 at post-transcriptional level. By in silico analysis, we discriminate the expression of miRNAs between tumor and normal tissue, finding miR-19a and miR-203 targeted to 3UTR-MAD2L1. Luciferase Assays proved that those miRs are specific to MAD2L1 in human cells. RT-qPCR showed an inverse correlation between the expression miRNA19 and 203 and MAD2L1 in a panel of gastric cancer cell lines and in a pilot series of patients. The miR-19a expression reduces the migration ability of AGS cells and invasion in MKN45 cells. Furthermore, the expression of the miRNA in combination with mitotic checkpoint drugs increase apoptosis. Finally, the TCGA analysis showed that Gastric Cancer patients with overexpression of MAD2, showed higher overall survival when miR-19a was overexpressed. Together, our results defined miR-19a as a critical regulator of MAD2 protein in Gastric Cancer and could potentially be used as a prognostic biomarker in clinical use.
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