Artículo
Selenocoumarins as new multitarget antiproliferative agents: Synthesis, biological evaluation and in silico calculations
Autor/es | Lagunes, Irene
Begines Aguilar, Paloma Silva, Adrián Galán, Alexis R. Puerta, Adrián Fernandes, Miguel X. Maya Castilla, Inés Fernández-Bolaños Guzmán, José María López López, Óscar Padrón, José M. |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2019-10-01 |
Fecha de depósito | 2024-02-06 |
Publicado en |
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Resumen | Herein we report a straightforward preparation of new antiproliferative agents based on the hybridization of a coumarin skeleton and an organoselenium motif. Three families were obtained: isoselenocyanate, selenocarbamates ... Herein we report a straightforward preparation of new antiproliferative agents based on the hybridization of a coumarin skeleton and an organoselenium motif. Three families were obtained: isoselenocyanate, selenocarbamates and selenoureas. The main purpose of these hybrid structures is the development of new antiproliferative agents with a multitarget mode of action. A strong correlation between the nature of the organosenium scaffold and the antiproliferative activity was observed. Thus, whereas selenocarbamates proved to be inactive, or moderate antiproliferative agents, isoselenocyanate and most of the selenoureas behaved as strong antiproliferative agents, with GI50 values within the low micromolar range. Interestingly, a good selectivity toward tumor cell lines was found for some of the compounds. Moreover, an increase in the ROS level was observed for tumor cells, and accordingly, these pro-oxidant species might be involved in their mode of action. Overall, title compounds were found not to be substrates for P-glycoprotein, which is overexpressed in many cancer cells as a way of detoxification, and thus, to develop drug resistance. In silico calculations revealed that the selenoderivatives prepared herein might undergo a strong interaction with the active site of HDAC8, and therefore, be potential inhibitors of histone deacetylase 8. In vitro assessment against HDAC8 revealed a strong inhibition of such enzyme exerted by selenoureas, particularly by symmetrical coumarin-containing selenourea. Two compounds showed good antiproliferative data and appear as plausible leads for further testings. The symmetrical coumarin 6 displays the best in vitro inhibition of HDAC8, but is affected by P-gp. In contrast, the N-butyl selenourea coumarin derivative 5a escapes P-gp resistance but has lower HDAC8 inhibition activity. |
Agencias financiadoras | Ministerio de Ciencia e Innovación (MICIN). España Junta de Andalucía European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) |
Identificador del proyecto | CTQ2016-78703-P
PGC2018-094503-B-C22 FQM134 501100008530 |
Cita | Lagunes, I., Begines Aguilar, P., Silva, A., Galán, A.R., Puerta, A., Fernandes, M.X.,...,Padrón, J.M. (2019). Selenocoumarins as new multitarget antiproliferative agents: Synthesis, biological evaluation and in silico calculations. European Journal of Medicinal Chemistry, 179, 493-501. https://doi.org/10.1016/j.ejmech.2019.06.073. |
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Selenocoumarins_C.pdf | 1.684Mb | [PDF] | Ver/ | Versión aceptada |