Synthesis of a novel analog of calcitriol and its biological evaluation as antitumor agent

ALONSO, ELIANA NOELIA; MASCARÓ, MARILINA; GÓMEZ, GENEROSA; CURINO, ALEJANDRO CARLOS; OBIOL, DIEGO JAVIER; GRIOLI, SILVINA MARIELA; MARTÍNEZ, ANDREA; QUEVEDO, MARIO ALFREDO; FERRONATO, MARÍA JULIA; GUEVARA, JOSEFINA ALEJANDRA; RIVADULLA, MARCOS LOIS; FALL, YAGAMARE; FACCHINETTI, MARÍA MARTA

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2019 vol. 185 p. 118 - 136

0960-0760

Calcitriol analogs have shown promising potential as compounds to be used in cancer chemotherapy. This report presents the synthesis of a novel vitamin D3 derivative with an amide and a carboxyl group in its side chain, called ML-344. In addition, we report its in vitro antitumor activity and its in vivo calcemic effects. We demonstrate that the analog decreases cell viability and retards cell migration of different breast, glioblastoma and head and neck cancer cell lines. Additionally, unlike calcitriol, ML-344 does not display citotoxicity to the murine non-malignant mammary cells and human astrocytes. In concordance with the antimigratory effects found in breast cancer cells, ML-344 decreased the invasive capacity and induced a rearrangement of the actin cytoskeleton in the LM3 breast cancer cell line. In relation to the in vivo studies, the analog did not cause hypercalcemic effects in CF1 mice administered daily at 5ìg/Kg of body weight during a period of 264h. Finally, computational studies were performed to evaluate the potential binding of the analog to the vitamin D receptor and the in silico assays showed that ML-344 is able to bind to VDR with interesting particularities and greater affinity than calcitriol. Altogether, these results suggest that ML344has a promising potential as an antitumor agent with a differential effect between tumor and non-malignant cells.