Síntese, avaliação do potencial antitumoral in vitro e docking molecular de novas imino - chalconas candidatas a inibidoras de CDK2
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2022-02-11
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Universidade Federal de Goiás
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The search for new active compounds is a line of research widely studied in the area of organic chemistry. Within this niche, computational tools, such as molecular docking, gain great importance for shortening and being able to assertively predict the discoveries of new drugs, as well as the repositioning of these. Among the classes of natural products that receive enormous attention in this field, the chalcones and their derivatives stand out, as they have diverse applicability and have an attractive structural scafford for structural modifications. The objective of this work was the synthesis of derivatives of chalcones, evaluation of the profile of tumor inhibition against the cell lines SNB-19 (Glioblastoma), PC-3 (Prostate), HCT-116 (Colon) and HL-60 (leukemia) and the search for biological targets for the synthesized products, with the purpose of applying the molecular docking process. Seven compounds were synthesized with yields ranging from 25% to 43%, where 5 of these were not published (M1, M4, M5, M6 and M7). The synthesized imino chalcones were tested in vitro against the four cancer cell lines showing an inhibition profile above 75% for all lines, especially the HL-60 line where all compounds showed an inhibition profile above 99%. Compound M4 had the lowest IC50 value, 5.5 µM, for the HL-60 strain. The identification of molecular targets was performed using the PharmMapper platform, where two possible targets were identified, these being the proteins DAPK3 and CDK2. The docking process was validated using the redcoking of the co-crystallization ligands, with the parameters previously defined, where the validity of the process was demonstrated, noting a mean square deviation (RMSD) value close to the crystallographic data, both smaller than 2 Å, where the value found for CDK2 was 0.099 Å. The docking results indicate that the imino-chalcones had a higher affinity for the CDK2 protein, where the compound M4 had the best affinity value (-10.0 Kcal/mol), interacting with some key residues of the CDK2 enzyme by hydrogen bonding with Leu83 and π-anion with Asp145. The ADME profile shows that imino-chalcones have good gastrointestinal absorption, with the exception of compounds M1 and M3. The compounds inhibit CYP3A4, with the exception of M1, in addition to being substrated from p-glycoprotein (Pg-p), minus M2, indicating that an optimization of the structures is necessary to improve their ADME properties.
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ANJOS, M. M. Síntese, avaliação do potencial antitumoral in vitro e docking molecular de novas imino - chalconas candidatas a inibidoras de CDK2. 2022. 130 f. Tese (Doutorado em Química) - Universidade Federal de Goiás, Goiânia, 2022.