Journal article

Synthesis and Biological Evaluation of 1 alpha,25-Dihydroxyvitamin D-3 Analogues with a Long Side Chain at C12 and Short C17 Side Chains

Diego M Carballa, Samuel Seoane, Flavia Zacconi, Xenxo Perez, Antonio Rumbo, Silvia Alvarez-Diaz, Maria Jesus Larriba, Roman Perez-Fernandez, Alberto Munoz, Miguel Maestro, Antonio Mourino, Mercedes Torneiro

JOURNAL OF MEDICINAL CHEMISTRY | AMER CHEMICAL SOC | Published : 2012

Abstract

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 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 D₃ analogues bound less strongly to the VDR than 1α,25-dihydroxyvitamin D₃ but had similar antiproliferative, pro-differ..

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Grants

Awarded by Spanish Ministry of Education and Innovation


Funding Acknowledgements

We thank the Spanish Ministry of Education and Innovation (SAF2007-67205 and SAF2010-15291 to A. Mourino, SAF2010-18302 to A. Munoz, and SAF2009-07631 to RPF) for financial support and CESGA for computer time. S.S. thanks the Fundacion Cientifica de la Asociacion Espanola Contra el Cancer for a postdoctoral fellowship. F.Z. thanks the Universidad Nacional del Sur (Argentina) for financial support. We thank Dishman-Netherlands for the generous gift of vitamin D<INF>2</INF> and Dr. Fredy Sussman for advice on docking studies.