Synthesis and biological evaluation of 1alpha,25-dihydroxyvitamin D(3) analogues with a long side chain at C12 and short C17 side chains.

Article Details

Citation

Carballa DM, Seoane S, Zacconi F, Perez X, Rumbo A, Alvarez-Diaz S, Larriba MJ, Perez-Fernandez R, Munoz A, Maestro M, Mourino A, Torneiro M

Synthesis and biological evaluation of 1alpha,25-dihydroxyvitamin D(3) analogues with a long side chain at C12 and short C17 side chains.

J Med Chem. 2012 Oct 25;55(20):8642-56. doi: 10.1021/jm3008272. Epub 2012 Oct 4.

PubMed ID
22989379 [ View in PubMed
]
Abstract

Structure-guided optimization was used to design new analogues of 1alpha,25-dihydroxyvitamin D(3) bearing the main side chain at C12 and a shorter second hydroxylated chain at C17. The new compounds 5a-c 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 D(3) analogues bound less strongly to the VDR than 1alpha,25-dihydroxyvitamin D(3) but had similar antiproliferative, pro-differentiating, and transcriptional activity as the native hormone. In vivo, the three analogues had markedly low calcemic effects.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CalcitriolVitamin D3 receptorIC 50 (nM)1.24N/AN/ADetails
CalcitriolVitamin D3 receptorEC 50 (nM)3.28N/AN/ADetails