Cytotoxic Activity, Topoisomerase I Inhibition and In Silico Studies of New Sesquiterpene-aryl Ester Derivatives of (-) Drimenol

Ileana Araque, Javiera Ramírez, Rut Vergara, Jaime Mella, Pablo Aránguiz, Luis Espinoza, Waleska Vera, Iván Montenegro, Cristian O. Salas, Joan Villena, Mauricio A. Cuellar

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

Resumen

In this study, we aimed to evaluate two sets of sesquiterpene-aryl derivatives linked by an ester bond, their cytotoxic activities, and their capacity to activate caspases 3/7 and inhibit human topoisomerase I (TOP1). A total of 13 compounds were synthesized from the natural sesquiterpene (-)-drimenol and their cytotoxic activity was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and an immortalized non-tumoral cell line (MCF-10). From the results, it was observed that 6a was the most promising compound due to its cytotoxic effect on three cancer cell lines and its selectivity, 6a was 100-fold more selective than 5-FU in MCF-7 and 20-fold in PC-3. It was observed that 6a also induced apoptosis by caspases 3/7 activity using a Capsase-Glo-3/7 assay kit and inhibited TOP1. A possible binding mode of 6a in a complex with TOP1-DNA was proposed by docking and molecular dynamics studies. In addition, 6a was predicted to have a good pharmacokinetic profile for oral administration. Therefore, through this study, it was demonstrated that the drimane scaffold should be considered in the search of new antitumoral agents.

Idioma originalInglés
Número de artículo3959
PublicaciónMolecules
Volumen28
N.º9
DOI
EstadoPublicada - may. 2023

Áreas temáticas de ASJC Scopus

  • Química analítica
  • Química (miscelánea)
  • Medicina molecular
  • Ciencias farmacéuticas
  • Descubrimiento de medicamentos
  • Química física y teórica
  • Química orgánica

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