Novel Calcitriol Analog with an Oxolane Group: in Vitro, in Vivo and in Silico Studies.

OBIOL DJ; MARTINEZ DOMINGUEZ A; FERRONATO MJ; QUEVEDO MA; GRIOLI SM; ALONSO EN; GOMEZ G; FALL Y; FACCHINETTI MM; CURINO AC

ARCHIV DER PHARMAZIE.

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2019 vol. 352

0365-6233

The active form of vitamin D3, calcitriol, is a potent antiproliferative compund. However, when effective antitumor doses of calcitriol are employed, hypercalcemic effects are observed, thus blocking its therapeutic application. To overcome this problem, structural analogues have been designed with the aim at retaining or even increasing the antitumor effects while decreasing its calcemic activity. This report aims at gaining insight into the structure/activity relationships of the novel oxolane -containing analogue (AM-27) recently synthesized. We herein demonstrate that this compound has anti-proliferative and anti-migratory effects in squamous cell carcinoma, glioblastoma and breast cancer cell lines. Analyses of the mechanisms underlying AM-27 effects on cell viability revealed an induction of apoptosis by the analogue. Importantly, non-malignant 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 human VDR with a higher affinity than the natural ligand calcitriol, feature that is mostly derived from an electrostatic interaction pattern. Altogether, the pro-apoptotic 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 therapeutic compound for cancer treatment.