• Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivatives
Different studies have shown that aberrant activation of the Hedgehog (Hh) signaling pathway could be involved in the origin of several types of human cancer, including lung, colon, and pancreas. In addition, numerous studies showed that different small molecules have an inhibitory effect on the Hh...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | Chile |
| OAI Identifier: | oai:repositorio.anid.cl:10533/253004 |
| Acceso en línea: | https://hdl.handle.net/10533/253004 |
| Access Level: | acceso abierto |
| Palabra clave: | Ciencias Naturales Ciencias Químicas Química Orgánica |
| Sumario: | Different studies have shown that aberrant activation of the Hedgehog (Hh) signaling pathway could be involved in the origin of several types of human cancer, including lung, colon, and pancreas. In addition, numerous studies showed that different small molecules have an inhibitory effect on the Hh signaling pathway. Specifically, these Hh modulators target the Smoothened (Smo) receptor. An example of this is the drug vismodegib, a Smo antagonist, used to treat basal cell carcinoma and medulloblastoma. However, in recent reports, resistance to this drug has been detected due to new mutations in Smo, which requires the development of new, more efficient ligands. Based on the above, in this thesis, new fifty 2,6,9-trisubstituted purine derivatives (Series I and II) were designed and synthesized based on fragments of Smo bioactive molecules. Synthetic methodologies to obtain these new compounds involved classical organic chemistry reactions. The compounds obtained were structurally characterized through different techniques. Also, cell viability was evaluated in pancreatic cancer lines, medulloblastoma, and no-neoplastic cells. These were compared with the controls vismodegib and gemcitabine, the latter used to treat pancreatic adenocarcinoma, showing that ten ligands of Series II presented an IC50 value of less than 10 μM in different pancreatic cancer cell lines. However, only four of these (11c, 16c, 16g, and 16f) presented a good selectivity index for this cancer. On the other hand, the ligands of Series I did not was determined their cytotoxicity, due to their low solubilities. A bioinformatic study to determine the different binding modes of the Series II ligands with the receptor was carried out, realizing that several of these ligands have hydrogen-bridge-type interactions with amino acids of the binding site expected in this study. For Series I ligands, a reverse docking study was carried out to find a suitable pharmacological model for this type of ligands, where adenosine A1 receptor was one of them. |
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