American Chemical Society
jm3008272_si_001.pdf (11.42 MB)

Synthesis and Biological Evaluation of 1α,25-Dihydroxyvitamin D3 Analogues with a Long Side Chain at C12 and Short C17 Side Chains

Download (11.42 MB)
journal contribution
posted on 2016-02-20, 07:52 authored by Diego M. Carballa, Samuel Seoane, Flavia Zacconi, Xenxo Pérez, Antonio Rumbo, Silvia Alvarez-Díaz, María Jesús Larriba, Román Pérez-Fernández, Alberto Muñoz, Miguel Maestro, Antonio Mouriño, Mercedes Torneiro
Structure-guided optimization was used to design new analogues of 1α,25-dihydroxyvitamin D3 bearing the main side chain at C12 and a shorter second hydroxylated chain at C17. The new compounds 5ac were efficiently synthesized from ketone 9 (which is readily accessible from the Inhoffen–Lythgoe diol) with overall yields of 15%, 6%, and 3% for 5a, 5b, and 5c, respectively. The triene system was introduced by the Pd-catalyzed tandem cyclization–Suzuki coupling method. The new analogues were assayed against human colon and breast cancer cell lines and in mice. All new vitamin D3 analogues bound less strongly to the VDR than 1α,25-dihydroxyvitamin D3 but had similar antiproliferative, pro-differentiating, and transcriptional activity as the native hormone. In vivo, the three analogues had markedly low calcemic effects.