Submit Manuscript  

Article Details


Structure-Activity Relationship Study of an Alkynylphosphonate and Vynilphosphonate Analogues of Calcitriol

Author(s):

Silvina Mariela Grioli, Eliana Noelia Alonso, Evangelina Mascaró, Santiago Armando Stabile, María Julia Ferronato, Mario Alfredo Quevedo, Gabriel Radivoy, María Marta Facchinetti, Cristian Alejandro Vitale and Alejandro Carlos Curino*   Pages 1 - 17 ( 17 )

Abstract:


Background: 1α,25-dihydroxyvitamin D3 (calcitriol) shows potent growth-inhibitory properties on different can-cer cell lines but its hypercalcemic effects have severely hampered its therapeutic application. Therefore, it is important todevelop synthetic calcitriol analogues that retain or even increase its antitumoral effects and lack hypercalcemic activity. Based on previous evidence of the potent antitumor effects of the synthetic alkynylphosphonate EM1 analogue, we have now synthesized a derivative called SG.

Objective: The aim of the present work is to evaluate the calcemic activity and the antitumor effect of SG, comparing these effects with those exerted by calcitriol and with those previously published for EM1. In addition, we propose to analyse by in silico studies the chemical structure-biological function relationship of these molecules.

Methods: We performed the synthesis of vinylphosphonate SG analogue; in vitro assays on different cancer cell lines; in vivo assays on mice; and in silico assays applying computational molecular modelling.

Results: The SG compound lacks hypercalcemic activity, similar to the parent compound EM1. However, the antitumor ac-tivity was blunted, as no antiproliferative or antimigratory effects were observed. By in silico assays, we demostrated that SG analogue has lower affinity for the VDR-ligand binding domain than EM1 compound, due to lack of interaction with the important residues His305 and His397.

Conclusion: These results demonstrate that chemical modification in the lateral side chain of the SG analogue affects the antitumoral activity observed previously for EM1 but does not affect the calcemic activity. These results contribute to the rational design and synthesis of novel calcitriol analogues.

Keywords:

Calcitriol, Phosphonate Analogues, Cancer, Hypercalcemia, Synthesis, In vitro assays, In vivo assays, Computational Modelling.

Affiliation:

Laboratorio de Química Orgánica, Instituto de Química del Sur (INQUISUR), Universidad Nacional del Sur (UNS), CONICET, Departamento de Química (UNS), Bahía Blanca, 8000, Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)–CONICET, Departamento de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, 8000, Laboratorio de Química Orgánica, Instituto de Química del Sur (INQUISUR), Universidad Nacional del Sur (UNS), CONICET, Departamento de Química (UNS), Bahía Blanca, 8000, Laboratorio de Química Orgánica, Instituto de Química del Sur (INQUISUR), Universidad Nacional del Sur (UNS), CONICET, Departamento de Química (UNS), Bahía Blanca, 8000, Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)–CONICET, Departamento de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, 8000, Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA-CONICET), Facultad de Ciencias Químicas, Ciudad Universitaria, Universidad Nacional de Córdoba, Córdoba, 5000, Laboratorio de Química Orgánica, Instituto de Química del Sur (INQUISUR), Universidad Nacional del Sur (UNS), CONICET, Departamento de Química (UNS), Bahía Blanca, 8000, Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)–CONICET, Departamento de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, 8000, Laboratorio de Química Orgánica, Instituto de Química del Sur (INQUISUR), Universidad Nacional del Sur (UNS), CONICET, Departamento de Química (UNS), Bahía Blanca, 8000, Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)–CONICET, Departamento de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, 8000



Read Full-Text article