info:eu-repo/semantics/article
Novel calcitriol analogue with an oxolane group: In vitro, in vivo, and in silico studies
Fecha
2019-04-26Registro en:
Obiol, Diego Javier; Martínez, Andrea; Ferronato, María Julia; Quevedo, Mario Alfredo; Grioli, Silvina Mariela; et al.; Novel calcitriol analogue with an oxolane group: In vitro, in vivo, and in silico studies; Wiley VCH Verlag; Archiv Der Pharmazie; 352; 5; 26-4-2019; 1-10
0365-6233
1521-4184
CONICET Digital
CONICET
Autor
Obiol, Diego Javier
Martínez, Andrea
Ferronato, María Julia
Quevedo, Mario Alfredo
Grioli, Silvina Mariela
Alonso, Eliana Noelia
Gómez, Generosa
Fall, Yagamare
Facchinetti, Maria Marta
Curino, Alejandro Carlos
Resumen
The active form of vitamin D3, calcitriol, is a potent antiproliferative compound. However, when effective antitumor doses of calcitriol are used, hypercalcemic effects are observed, thus blocking its therapeutic application. To overcome this problem, structural analogues have been designed with the aim of retaining or even increasing the antitumor effects while decreasing its calcemic activity. This report aims at gaining insights into the structure–activity relationships of the novel oxolane‐ containing analogue, AM‐27, recently synthesized. We herein demonstrate that this compound has antiproliferative and antimigratory effects in squamous cell carcinoma, glioblastoma, and breast cancer cell lines. Analyses of the mechanisms underlying the AM‐27 effects on cell viability revealed induction of apoptosis by the analogue. Importantly, nonmalignant cell lines were little or not affected by the compound. In addition, the analogue did not produce hypercalcemia in mice. Also, in silico studies involving docking and molecular dynamics techniques showed that AM‐27 is able to bind to the human vitamin D receptor with a higher affinity than the natural ligand calcitriol, a feature that is mostly derived from an electrostatic interaction pattern. Altogether, the proapoptotic effect observed in cancer cells, the lack of calcemic activity in mice, and the differential effects in normal cells suggest the potential of AM‐27 as a therapeutic compound for cancer treatment.